Malonamides and malonamide derivatives as modulators of chemokine receptor activity

ABSTRACT

The present application describes modulators of MCP-1 of formula (I): 
                         
or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.

CROSS REFERENCE TO RELATED APPLICATIONS

Under 35 USC §119(e)(1), this application claims the benefit of priorU.S. application Ser. No. 60/467,028, filed May 1, 2003.

FIELD OF THE INVENTION

This invention relates generally to modulators of chemokine receptoractivity, pharmaceutical compositions containing the same, and methodsof using the same as agents for treatment and prevention of inflammatorydiseases, allergic and autoimmune diseases, and in particular, asthma,rheumatoid arthritis, atherosclerosis, and multiple sclerosis.

BACKGROUND OF THE INVENTION

Chemokines are chemotactic cytokines, of molecular weight 6–15 kDa, thatare released by a wide variety of cells to attract and activate, amongother cell types, macrophages, T and B lymphocytes, eosinophils,basophils and neutrophils (reviewed in: Luster, New Eng. J. Med. 1998,338, 436–445 and Rollins, Blood 1997, 90, 909–928). There are two majorclasses of chemokines, CXC and CC, depending on whether the first twocysteines in the amino acid sequence are separated by a single aminoacid (CXC) or are adjacent (CC). The CXC chemokines, such asinterleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) andmelanoma growth stimulatory activity protein (MGSA) are chemotacticprimarily for neutrophils and T lymphocytes, whereas the CC chemokines,such as RANTES, MIP-1α, MIP-1β, the monocyte chemotactic proteins(MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (−1 and −2) arechemotactic for, among other cell types, macrophages, T lymphocytes,eosinophils, dendritic cells, and basophils. There also exist thechemokines lymphotactin-1, lymphotactin-2 (both C chemokines), andfractalkine (a CX₃C chemokine) that do not fall into either of the majorchemokine subfamilies.

The chemokines bind to specific cell-surface receptors belonging to thefamily of G-protein-coupled seven-transmembrane-domain proteins(reviewed in: Horuk, Trends Pharm. Sci. 1994, 15, 159–165) which aretermed “chemokine receptors.” On binding their cognate ligands,chemokine receptors transduce an intracellular signal though theassociated trimeric G proteins, resulting in, among other responses, arapid increase in intracellular calcium concentration, changes in cellshape, increased expression of cellular adhesion molecules,degranulation, and promotion of cell migration. There are at least tenhuman chemokine receptors that bind or respond to CC chemokines with thefollowing characteristic patterns (reviewed in Zlotnik and OshieImmunity 2000, 12, 121): CCR-1 (or “CKR-1” or “CC-CKR-1”) [MIP-1α,MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell 1993, 72, 415–425, andLuster, New Eng. J. Med. 1998, 338, 436–445); CCR-2A and CCR-2B (or“CKR-2A”/“CKR-2B” or “CC-CKR-2A”/“CC-CKR-2B”) [MCP-1, MCP-2, MCP-3,MCP-4, MCP-5] (Charo, et al., Proc. Natl. Acad. Sci. USA 1994, 91,2752–2756, and Luster, New Eng. J. Med. 1998, 338, 436–445); CCR-3 (or“CKR-3” or “CC-CKR-3”) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4](Combadiere, et al., J. Biol. Chem. 1995, 270, 16491–16494, and Luster,New Eng. J. Med. 1998, 338, 436–445); CCR-4 (or “CKR-4” or “CC-CKR-4”)[TARC, MDC] (Power, et al., J. Biol. Chem. 1995, 270, 19495–19500, andLuster, New Eng. J. Med. 1998, 338, 436–445); CCR-5 (or “CKR-5” OR“CC-CKR-5”) [MIP-1α, RANTES, MIP-1β](Sanson, et al., Biochemistry 1996,35, 3362–3367); CCR-6 (or “CKR-6” or “CC-CKR-6”) [LARC] (Baba, et al.,J. Biol. Chem. 1997, 272, 14893–14898); CCR-7 (or “CKR-7” or “CC-CKR-7”)[ELC] (Yoshie et al., J. Leukoc. Biol. 1997, 62, 634–644); CCR-8 (or“CKR-8” or “CC-CKR-8”) [I-309] (Napolitano et al., J. Immunol., 1996,157, 2759–2763); CCR-10 (or “CKR-10” or “CC-CKR-10”) [MCP-1, MCP-3](Bonini, et al., DNA and Cell Biol. 1997, 16, 1249–1256); and CCR-11[MCP-1, MCP-2, and MCP-4] (Schweickert, et al., J. Biol. Chem. 2000,275, 90550).

In addition to the mammalian chemokine receptors, mammaliancytomegaloviruses, herpesviruses and poxviruses have been shown toexpress, in infected cells, proteins with the binding properties ofchemokine receptors (reviewed in: Wells and Schwartz, Curr. Opin.Biotech. 1997, 8, 741–748). Human CC chemokines, such as RANTES andMCP-3, can cause rapid mobilization of calcium via these virally encodedreceptors. Receptor expression may be permissive for infection byallowing for the subversion of normal immune system surveillance andresponse to infection. Additionally, human chemokine receptors, such asCXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for theinfection of mammalian cells by microbes as with, for example, the humanimmunodeficiency viruses (HIV).

The chemokines and their cognate receptors have been implicated as beingimportant mediators of inflammatory, infectious, and immunoregulatorydisorders and diseases, including asthma and allergic diseases, as wellas autoimmune pathologies such as rheumatoid arthritis andatherosclerosis (reviewed in: P. H. Carter, Current Opinion in ChemicalBiology 2002, 6, 510; Trivedi, et al, Ann. Reports Med. Chem. 2000, 35,191; Saunders and Tarby, Drug Disc. Today 1999, 4, 80; Premack andSchall, Nature Medicine 1996, 2, 1174). For example, the chemokinemonocyte chemoattractant-1 (MCP-1) and its receptor CC ChemokineReceptor 2 (CCR-2) play a pivotal role in attracting leukocytes to sitesof inflammation and in subsequently activating these cells. When thechemokine MCP-1 binds to CCR-2, it induces a rapid increase inintracellular calcium concentration, increased expression of cellularadhesion molecules, cellular degranulation, and the promotion ofleukocyte migration. Demonstration of the importance of the MCP-1/CCR-2interaction has been provided by experiments with genetically modifiedmice. MCP-1 −/− mice had normal numbers of leukocytes and macrophages,but were unable to recruit monocytes into sites of inflammation afterseveral different types of immune challenge (Bao Lu, et al., J. Exp.Med. 1998, 187, 601). Likewise, CCR-2 −/− mice were unable to recruitmonocytes or produce interferon-γ when challenged with various exogenousagents; moreover, the leukocytes of CCR-2 null mice did not migrate inresponse to MCP-1 (Landin Boring, et al., J. Clin. Invest. 1997, 100,2552), thereby demonstrating the specificity of the MCP-1/CCR-2interaction. Two other groups have independently reported equivalentresults with different strains of CCR-2 −/− mice (William A. Kuziel, etal., Proc. Natl. Acad. Sci. USA 1997, 94, 12053, and Takao Kurihara, etal., J. Exp. Med. 1997, 186, 1757). The viability and generally normalhealth of the MCP-1 −/− and CCR-2 −/− animals is noteworthy, in thatdisruption of the MCP-1/CCR-2 interaction does not induce physiologicalcrisis. Taken together, these data lead one to the conclusion thatmolecules that block the actions of MCP-1 would be useful in treating anumber of inflammatory and autoimmune disorders. This hypothesis has nowbeen validated in a number of different animal disease models, asdescribed below.

It is known that MCP-1 is upregulated in patients with rheumatoidarthritis (Alisa Koch, et al., J. Clin. Invest. 1992, 90, 772–779).Moreover, several studies have demonstrated the potential therapeuticvalue of antagonism of the MCP-1/CCR2 interaction in treating rheumatoidarthritis. A DNA vaccine encoding MCP-1 was shown recently to amelioratechronic polyadjuvant-induced arthritis in rats (Sawsan Youssef, et al.,J. Clin. Invest. 2000, 106, 361). Likewise, inflammatory diseasesymptoms could be controlled via direct administration of antibodies forMCP-1 to rats with collagen-induced arthritis (Hiroomi Ogata, et al., J.Pathol. 1997, 182, 106), or streptococcal cell wall-induced arthritis(Ralph C. Schimmer, et al., J. Immunol. 1998, 160, 1466). Perhaps mostsignificantly, a peptide antagonist of MCP-1, MCP-1 (9–76), was shownboth to prevent disease onset and to reduce disease symptoms (dependingon the time of administration) in the MRL-lpr mouse model of arthritis(Jiang-Hong Gong, et al., J. Exp. Med. 1997, 186, 131).

It is known that MCP-1 is upregulated in atherosclerotic lesions, and ithas been shown that circulating levels of MCP-1 are reduced throughtreatment with therapeutic agents, plays a role in disease progression(Abdolreza Rezaie-Majd, et al, Arterioscler. Thromb. Vasc. Biol. 2002,22, 1194–1199). Four key studies have demonstrated the potentialtherapeutic value of antagonism of the MCP-1/CCR2 interaction intreating atherosclerosis. For example, when MCP-1 −/− mice are matedwith LDL receptor-deficient mice, an 83% reduction in aortic lipiddeposition was observed (Long Gu, et al., Mol. Cell 1998, 2, 275).Similarly, when MCP-1 was genetically ablated from mice which alreadyoverexpressed human apolipoprotein B, the resulting mice were protectedfrom atherosclerotic lesion formation relative to the MCP-1 +/+apoBcontrol mice (Jennifa Gosling, et al., J. Clin. Invest. 1999, 103, 773).Likewise, when CCR-2 −/− mice are crossed with apolipoprotein E −/−mice, a significant decrease in the incidence of atherosclerotic lesionswas observed (Landin Boring, et al, Nature 1998, 394, 894). Finally,when apolipoprotein E −/− mice are administered a gene encoding apeptide antagonist of CCR2, then lesion size is decreased and plaquestability is increased (W. Ni, et al. Circulation 2001, 103, 2096–2101).

It is known that MCP-1 is upregulated in human multiple sclerosis, andit has been shown that effective therapy with interferon b-1b reducesMCP-1 expression in peripheral blood mononuclear cells, suggesting thatMCP-1 plays a role in disease progression (Carla Iarlori, et al., J.Neuroimmunol. 2002, 123, 170–179). Other studies have demonstrated thepotential therapeutic value of antagonism of the MCP-1/CCR-2 interactionin treating multiple sclerosis; all of these studies have beendemonstrated in experimental autoimmune encephalomyelitis (EAE), theconventional animal model for multiple scelerosis. Administration ofantibodies for MCP-1 to animals with EAE significantly diminisheddisease relapse (K. J. Kennedy, et al., J. Neuroimmunol. 1998, 92, 98).Furthermore, two recent reports have now shown that CCR-2 −/− mice areresistant to EAE (Brian T. Fife, et al., J. Exp. Med. 2000, 192, 899;Leonid Izikson, et al., J. Exp. Med. 2000, 192, 1075).

It is known that MCP-1 is upregulated in patients who developbronchiolitis obliterans syndrome after lung transplantation (MartineReynaud-Gaubert, et al., J. of Heart and Lung Transplant., 2002, 21,721–730; John Belperio, et al., J. Clin. Invest. 2001, 108, 547–556). Ina murine model of bronchiolitis obliterans syndrome, administration ofan antibody to MCP-1 led to attenuation of airway obliteration;likewise, CCR2 −/− mice were resistant to airway obliteration in thissame model (John Belperio, et al., J. Clin. Invest. 2001, 108, 547–556).These data suggest that antagonism of MCP-1/CCR2 may be beneficial intreating rejection of organs following transplantation.

Other studies have demonstrated the potential therapeutic value ofantagonism of the MCP-1/CCR2 interaction in treating asthma.Sequestration of MCP-1 with a neutralizing antibody inovalbumin-challenged mice resulted in marked decrease in bronchialhyperresponsiveness and inflammation (Jose-Angel Gonzalo, et al., J.Exp. Med. 1998, 188, 157). It proved possible to reduce allergic airwayinflammation in Schistosoma mansoni egg-challenged mice through theadministration of antibodies for MCP-1 (Nicholas W. Lukacs, et al., J.Immunol. 1997, 158, 4398). Consistent with this, MCP-1 −/− micedisplayed a reduced response to challenge with Schistosoma mansoni egg(Bao Lu, et al., J. Exp. Med. 1998, 187, 601).

Other studies have demonstrated the potential therapeutic value ofantagonism of the MCP-1/CCR2 interaction in treating kidney disease.Administration of antibodies for MCP-1 in a murine model ofglomerularnephritis resulted in a marked decrease in glomerular crescentformation and deposition of type I collagen (Clare M. Lloyd, et al., J.Exp. Med. 1997, 185, 1371). In addition, MCP-1 −/− mice with inducednephrotoxic serum nephritis showed significantly less tubular damagethan their MCP-1 +/+counterparts (Gregory H. Tesch, et al., J. Clin.Invest. 1999, 103, 73).

One study has demonstrated the potential therapeutic value of antagonismof the MCP-1/CCR2 interaction in treating systemic lupus erythematosus.Crossing of MCP-1 −/− mice with MRL-FAS^(lpr) mice—the latter of whichhave a fatal autoimmune disease that is analogous to human systemiclupus erythematosus—results mice that have less disease and longersurvival than the wildtype MRL-FAS^(lpr) mice (Gregory H. Tesch, et al.,J. Exp. Med. 1999, 190, 1813).

One study has demonstrated the potential therapeutic value of antagonismof the MCP-1/CCR2 interaction in treating colitis. CCR-2 −/− mice wereprotected from the effects of dextran sodium sulfate-induced colitis(Pietro G. Andres, et al., J. Immunol. 2000, 164, 6303).

One study has demonstrated the potential therapeutic value of antagonismof the MCP-1/CCR2 interaction in treating alveolitis. When rats with IgAimmune complex lung injury were treated intravenously with antibodiesraised against rat MCP-1 (JE), the symptoms of alveolitis were partiallyaleviated (Michael L. Jones, et al., J. Immunol. 1992, 149, 2147).

One study has demonstrated the potential therapeutic value of antagonismof the MCP-1/CCR2 interaction in treating cancer. When immunodeficientmice bearing human breast carcinoma cells were treated with ananti-MCP-1 antibody, inhibition of lung micrometastases and increases insurvival were observed (Rosalba Salcedo, et al., Blood 2000, 96, 34–40).

One study has demonstrated the potential therapeutic value of antagonismof the MCP-1/CCR2 interaction in treating restinosis. Mice deficient inCCR2 showed reductions in the intimal area and in the intima/media ratio(relative to wildtype littermates) after injury of the femoral artery(Merce Roque, et al. Arterioscler. Thromb. Vasc. Biol. 2002, 22,554–559).

Other studies have provided evidence that MCP-1 is overexpressed invarious disease states not mentioned above. These reports providecorrelative evidence that MCP-1 antagonists could be useful therapeuticsfor such diseases. Two reports described the overexpression of MCP-1 inthe intestinal epithelial cells and bowel mucosa of patients withinflammatory bowel disease (H. C. Reinecker, et al., Gastroenterology1995, 108, 40, and Michael C. Grimm, et al., J. Leukoc. Biol. 1996, 59,804). Two reports describe the overexpression of MCP-1 rats with inducedbrain trauma (J. S. King, et al., J. Neuroimmunol. 1994, 56, 127, andJoan W. Berman, et al., J. Immunol. 1996, 156, 3017). Another study hasdemonstrated the overexpression of MCP-1 in rodent cardiac allografts,suggesting a role for MCP-1 in the pathogenesis of transplantarteriosclerosis (Mary E. Russell, et al. Proc. Natl. Acad. Sci. USA1993, 90, 6086). The overexpression of MCP-1 has been noted in the lungendothelial cells of patients with idiopathic pulmonary fibrosis (HarryN. Antoniades, et al., Proc. Natl. Acad. Sci. USA 1992, 89, 5371).Similarly, the overexpression of MCP-1 has been noted in the skin frompatients with psoriasis (M. Deleuran, et al., J. Dermatol. Sci. 1996,13, 228, and R. Gillitzer, et al., J. Invest. Dermatol. 1993, 101, 127).Finally, a recent report has shown that MCP-1 is overexpressed in thebrains and cerebrospinal fluid of patients with HIV-1-associateddementia (Alfredo Garzino-Demo, WO 99/46991).

It should also be noted that CCR-2 has been implicated as a co-receptorfor some strains of HIV (B. J. Doranz, et al., Cell 1996, 85, 1149). Ithas also been determined that the use of CCR-2 as an HIV co-receptor canbe correlated with disease progression (Ruth I. Connor, et al., J. Exp.Med. 1997, 185, 621). This finding is consistent with the recent findingthat the presence of a CCR-2 mutant, CCR2-64I, is positively correlatedwith delayed onset of HIV in the human population (Michael W. Smith, etal., Science 1997, 277, 959). Although MCP-1 has not been implicated inthese processes, it may be that MCP-1 antagonists that act via bindingto CCR-2 may have beneficial therapeutic effects in delaying the diseaseprogression to AIDS in HIV-infected patients.

Recently, a number of groups have described the development of smallmolecule antagonists of MCP-1 (reviewed in: Bharat K. Trivedi, et al,Ann. Reports Med. Chem. 2000, 35, 191). Workers at Teijen and Combichemreported the use of cyclic amines (A) as MCP-1 (Tatsuki Shiota, et al.,WO 99/25686; Tatsuki Shiota, et al., WO 00/69815) and MIP-1α (ChristineTarby and Wilna Moree, WO 00/69820) antagonists. These compounds aredistinguished from those of the present invention (I) by the requirementfor the central cyclic amine grouping.

Workers at Bristol-Myers Squibb have reported the use of acyclicdiamines (B) as MCP-1 antagonists (Percy Carter and Robert Cherney,WO-02/50019).

Workers at Bristol-Myers Squibb have reported the use of cyclic diamines(C) as MCP-1 antagonists (Robert Cherney, WO-02/060859).

Workers at Pfizer have reported the use of bicyclic diamines (D) asMCP-1 antagonists (Roberto Colon-Cruz, et al., WO-02/070523).

A number of other groups have also described the development of smallmolecule antagonists of the MCP-1/CCR-2 interaction. To date,indolopiperidines (Ian T. Forbes, et al., Bioorg. Med. Chem. Lett. 2000,10, 1803), spiropiperidines (Tara Mirzadegan, et al., J. Biol. Chem.2000, 275, 25562), quaternary amines (Masanori Baba, et al., Proc. Natl.Acad. Sci. 1999, 96, 5698), 2-substituted indoles (Alan Faull and JasonKettle, WO 00/46196; Andrew John Barker, et al., WO 99/07351; AndrewJohn Barker, et al., WO 99/07678), pyrazolone derivatives (JanakKhimchand Padia, et al., U.S. Pat. No. 6,011,052, 2000), 2-substitutedbenzimidazoles (David Thomas Connor, et al., WO 98/06703),N,N-dialkylhomopiperazines (T. Shiota, et al., WO 97/44329), bicyclicpyrroles (Andrew J. Barker, et al., WO 99/40913 and Andrew J. Barker, etal., WO 99/40914), and 5-aryl pentadienamides (K. G. Carson, et al.,Cambridge Health Tech Institute Chemokine Symposium, McLean, Va., USA,1999) have all been reported as MCP-1 antagonists.

The foregoing reference compounds are readily distinguished structurallyfrom the present invention. The prior art does not disclose nor suggestthe unique combination of structural fragments that embody the novelcompounds described herein. Furthermore, the prior art does not discloseor suggest that the compounds of the present invention would beantagonists of MCP-1.

It should be noted that CCR-2 is also the receptor for the chemokinesMCP-2, MCP-3, MCP-4, and MCP-5 (Luster, New Eng. J. Med. 1998, 338,436–445). Since the new compounds of formula (I) described hereinantagonize MCP-1 by binding to the CCR-2 receptor, it may be that thesecompounds of formula (I) are also effective antagonists of the actionsof MCP-2, MCP-3, MCP-4, and MCP-5 that are mediated by CCR-2.Accordingly, when reference is made herein to “antagonism of MCP-1,” itis to be assumed that this is equivalent to “antagonism of chemokinestimulation of CCR-2.”

SUMMARY OF THE INVENTION

Accordingly, the present invention provides novel antagonists or partialagonists/antagonists of MCP-1 receptor activity, or pharmaceuticallyacceptable salts or prodrugs thereof.

The present invention provides pharmaceutical compositions comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of at least one of the compounds of the present invention or apharmaceutically acceptable salt or prodrug form thereof.

The present invention provides a method for treating rheumatoidarthritis, multiple sclerosis, and atherosclerosis, comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a pharmaceutically acceptable salt or prodrug form thereof.

The present invention provides a method for treating inflammatorydiseases, comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a pharmaceutically acceptable salt or prodrug formthereof.

The present invention provides novel compounds for use in therapy.

The present invention provides the use of novel compounds for themanufacture of a medicament for the treatment of inflammatory diseases.

These and other features of the invention, which will become apparentduring the following detailed description, have been achieved by theinventors' discovery that compounds of formula (I):

or stereoisomers or pharmaceutically acceptable salts thereof, whereinX, Z, m, n, 1, R¹, R², R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹⁴, andR^(14a) are defined below, are effective modulators of chemokineactivity.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

[1] Thus, in a first embodiment, the present invention provides novelcompounds of formula (I):

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein:

-   Z is selected from a bond, —C(O)—, and —C(O)NR¹⁸;-   Q is selected from O or S;-   X is —CHR¹⁶NR¹⁷—;-   R^(a) is selected from H, methyl, and ethyl;-   R¹ is selected from a C₆₋₁₀ aryl group substituted with 0–5 R⁴ and a    5–10 membered heteroaryl system containing 1–4 heteroatoms selected    from N, O, and S, substituted with 0–3 R⁴;-   R² is selected from a C₆₋₁₀ aryl group substituted with 0–5 R⁵ and a    5–10 membered heteroaryl system containing 1–4 heteroatoms selected    from N, O, and S, substituted with 0–3 R⁵;-   R³ is selected from H, (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(3d),    (CRR)_(q)S(O)_(p)R^(3d), (CRR)_(r)C(O)R^(3b),    (CRR)_(q)NR^(3a)R^(3a), (CRR)_(r)C(O)NR^(3a)R^(3a),    (CRR)_(r)C(O)NR^(3a)OR^(3d), (CRR)_(q)SO₂NR^(3a)R^(3a),    (CRR)_(r)C(O)OR^(3d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0–5 R^(3e), and a (CRR)_(r)-5–10 membered    heterocyclic system containing 1–4 heteroatoms selected from N, O,    and S, substituted with 0–3 R^(3e);-   with the proviso that R³ is not H if R⁶ is H;-   alternatively, R³ and R¹² join to form a C₃₋₆ cycloalkyl substituted    with 0–2 R^(3g), a 5–6 membered lactam ring in which carbon atoms of    the ring are substituted with 0–2 R^(3g), or a 5–6 membered lactone    ring in which carbon atoms of the ring are substituted with 0–2    R^(3g);-   R^(3a), at each occurrence, is independently selected from H, methyl    substituted with 0–1 R^(3c), C₂₋₆ alkyl substituted with 0–3 R^(3e),    C₃₋₈ alkenyl substituted with 0–3 R^(3e), C₃₋₈ alkynyl substituted    with 0–3 R^(3e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0–5 R^(3e), and a    (CH₂)_(r)-5–10 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(3e);-   R^(3b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0–3 R^(3e), C₂₋₈ alkenyl substituted with 0–3    R^(3e), C₂₋₈ alkynyl substituted with 0–3 R^(3e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0–2 R^(3e), and a (CH₂)_(r)-5–6    membered heterocyclic system containing 1–4 heteroatoms selected    from N, O, and S, substituted with 0–3 R^(3e);-   R^(3c) is independently selected from —C(O)R^(3b), —C(O)OR^(3d),    —C(O)NR^(3f)R^(3f), and (CH₂)_(r)phenyl;-   R^(3d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0–3 R^(3e), C₃₋₆ alkenyl    substituted with 0–3 R^(3e), C₃₋₆ alkynyl substituted with 0–3    R^(3e), a C₃₋₁₀ carbocyclic residue substituted with 0–3 R^(3e), and    a (CH₂)_(r)-5–6 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(3e);-   R^(3e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,    (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,    (CH₂)_(r)NR^(3f)R^(3f), and (CH₂)_(r)phenyl;-   R^(3f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆    cycloalkyl;-   R^(3g) is selected from (CHR)_(r)OH, (CHR)_(r)SH, (CHR)_(r)OR^(3d),    (CHR)_(r)S(O)_(r)R^(3d), (CHR)_(r)C(O)R^(3b),    (CHR)_(r)NR^(3a)R^(3a), (CHR)_(r)C(O)NR^(3a)R^(3a),    (CHR)_(r)C(O)NR^(3a)OR^(3d), (CHR)_(r)SO₂NR^(3a)R^(3a),    (CHR)_(r)C(O)OR^(3d), and a (CHR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0–5 R^(3e);-   R, at each occurrence, is independently selected from H, C₁₋₆ alkyl,    C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl,    (CHR)_(r)C(O)NR^(3a)R^(3a), and (CHR)_(r)C(O)OR^(3d), and    (CH₂)_(r)phenyl substituted with 0–3 R^(3e), and a (CH₂)_(r)-5–10    membered heterocyclic system containing 1–4 heteroatoms selected    from N, O, and S, substituted with 0–3 R^(3e);-   R⁴, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(4a)R^(4a), (CR′R′)_(r)OH,    (CR′R′)_(r)(CR′R′)_(r)R^(4d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(4d), (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)    (CR′R′)_(r)R^(4b), (CR′R′)_(r)C(O)NR^(4a)R^(4a),    (CR′R′)_(r)NR^(4f)C(O) (CR′R′)_(r)R^(4b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(4d), (CR′R′)_(r)OC(O)    (CR′R′)_(r)R^(4b), (CR′R′)_(r)NR^(4f)C(O)O(CR′R′)_(r)R^(4d),    (CR′R′)_(r)OC(O)NR^(4a)R^(4a),    (CR′R′)_(r)NR^(4a)C(S)NR^(4a)(CR′R′)_(r)R^(4d),    (CR′R′)_(r)NR^(4a)C(O)NR^(4a)R^(4a),    (CR′R′)_(r)C(═NR^(4f))NR^(4a)R^(4a),    (CR′R′)_(r)NHC(═NR^(4f))NR^(4f)R^(4f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(4b), (CR′R′)_(r)S(O)₂NR^(4a)R^(4a),    (CR′R′)_(r)NR^(4f)S(O)₂NR^(4a)R^(4a), (CR′R′)_(r)NR^(4f)S(O)₂    (CR′R′)_(r)R^(4b), C₁₋₆ haloalkyl, C₂₋₈ alkenyl substituted with 0–3    R′, C₂₋₈ alkynyl substituted with 0–3 R′, and (CR′R′)_(r)phenyl    substituted with 0–3 R^(4e);-   alternatively, two R⁴ on adjacent atoms on R¹ may join to form a    cyclic acetal;-   R^(4a), at each occurrence, is independently selected from H, methyl    substituted with 0–1 R^(4g), C₂₋₆ alkyl substituted with 0–2 R^(4e),    C₃₋₈ alkenyl substituted with 0–2 R^(4e), C₃₋₈ alkynyl substituted    with 0–2 R^(4e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0–5 R^(4e), and a (CH₂)_(r)-5–10 membered heterocyclic system    containing 1–4 heteroatoms selected from N, O, and S, substituted    with 0–2 R^(4e);-   R^(4b), at each occurrence, is selected from C₁₋₆ alkyl substituted    with 0–2 R^(4e), C₃₋₈ alkenyl substituted with 0–2 R^(4e), C₃₋₈    alkynyl substituted with 0–2 R^(4e), a (CH₂)_(r)C₃₋₆ carbocyclic    residue substituted with 0–3 R^(4e), and a (CH₂)_(r)-5–6 membered    heterocyclic system containing 1–4 heteroatoms selected from N, O,    and S, substituted with 0–2 R^(4e);-   R^(4d), at each occurrence, is selected from C₃₋₈ alkenyl    substituted with 0–2 R^(4e), C₃₋₈ alkynyl substituted with 0–2    R^(4e), methyl, CF₃, C₂₋₆ alkyl substituted with 0–3 R^(4e), a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0–3 R^(4e), and    a (CH₂)_(r)-5–6 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(4e);-   R^(4e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;-   R^(4f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   R^(4g) is independently selected from —C(O)R^(4b), —C(O)OR^(4d),    —C(O)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;-   R⁵, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(5a)R^(5a), (CR′R′)_(r)OH, (CR′R′)_(r)°    (CR′R′)_(r)R^(5d), (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H,    (CR′R′)_(r)S(CR′R′)_(r)R^(5d), (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)    (CR′R′)_(r)R^(5b), (CR′R′)_(r)C(O)NR^(5a)R^(5a),    (CR′R′)_(r)NR^(5f)C(O) (CR′R′)_(r)R^(5b),    (CR′R′)_(r)C(O)O(CR′R′)_(r)R^(5d), (CR′R′)_(r)OC(O)    (CR′R′)_(r)R^(5b), CR′R′)_(r)NR^(5f)C(O)O(CR′R′)_(r)R^(5d),    (CR′R′)_(r)OC(O)NR^(5a)R^(5a), (CR′R′)_(r)NR^(5a)C(O)NR^(5a)R^(5a),    (CR′R′)_(r)C(═NR^(5f))NR^(5a)R^(5a),    (CR′R′)_(r)NHC(═NR^(5f))NR^(5f)R^(5f),    (CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(5b), (CR′R′)_(r)S(O)₂NR^(5a)R^(5a),    (CR′R′)_(r)NR^(5a)S(O)₂NR^(5a)R^(5a), (CR′R′)_(r)NR^(5f)S(O)₂    (CR′R′)_(r)R^(5b)C₁₋₆ haloalkyl, C₂₋₈ alkenyl substituted with 0–3    R′, C₂₋₈ alkynyl substituted with 0–3 R′, (CR′R′)_(r)phenyl    substituted with 0–3 R^(5e), and a (CRR)_(r)-5–10 membered    heterocyclic system containing 1–4 heteroatoms selected from N, O,    and S, substituted with 0–2 R^(5c);-   alternatively, two R⁵ on adjacent atoms on R² may join to form a    cyclic acetal;-   R^(5a), at each occurrence, is independently selected from H, methyl    substituted with 0–1 R^(5g), C₂₋₆ alkyl substituted with 0–2 R^(5e),    C₃₋₈ alkenyl substituted with 0–2 R^(5e), C₃₋₈ alkynyl substituted    with 0–2 R^(5e), a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted    with 0–5 R^(5e), and a (CH₂)_(r)-5–10 membered heterocyclic system    containing 1–4 heteroatoms selected from N, O, and S, substituted    with 0–2 R^(5e);-   R^(5b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0–2 R^(5e), C₃₋₈ alkenyl substituted with 0–2    R^(5e), C₃₋₈ alkynyl substituted with 0–2 R^(5e), a (CH₂)_(r)C₃₋₆    carbocyclic residue substituted with 0–3 R^(5e), and a (CH₂)_(r)-5–6    membered heterocyclic system containing 1–4 heteroatoms selected    from N, O, and S, substituted with 0–2 R^(5e);-   R^(5d), at each occurrence, is independently selected from C₃₋₈    alkenyl substituted with 0–2 R^(5e), C₃₋₈ alkynyl substituted with    0–2 R^(5e), methyl, CF₃, C₂₋₆ alkyl substituted with 0–3 R^(5e), a    (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0–3 R^(5e), and    a (CH₂)_(r)-5–6 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(5e);-   R^(5e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;-   R^(5f), at each occurrence, is selected from H, C₁₋₅ alkyl, and C₃₋₆    cycloalkyl, and phenyl;-   R^(5g) is independently selected from —C(O)R^(5b), —C(O)OR^(5d),    —C(O)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;-   R′, at each occurrence, is selected from H, C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl    substituted with R^(5e);-   R⁶, is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(6d), (CRR)_(q)S(O)_(p)R^(6d),    (CRR)_(r)C(O)R^(6b), (CRR)_(r)NR^(6a)R^(6a),    (CRR)_(r)C(O)NR^(6a)R^(6a), (CRR)_(r)C(O)NR^(6a)OR^(6d),    (CRR)SO₂NR^(6a)R^(6a), (CRR)_(r)C(O)OR^(6d), a (CRR)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0–5 R^(6e), and a    (CRR)_(r)-5–10 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(6e);-   alternatively, R⁶ and R⁷ join to form a C₃₋₆ cycloalkyl substituted    with 0–2 R^(6g), a 5–6 membered ring lactam substituted with 0–2    R^(6g), or a 5–6 membered ring lactone substituted with 0–2 R^(6g);-   R^(6a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0–3 R^(6e), C₃₋₈ alkenyl    substituted with 0–3 R^(6e), C₃₋₈ alkynyl substituted with 0–3    R^(6e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0–5 R^(6e), and a (CH₂)_(r)-5–10 membered    heterocyclic system containing 1–4 heteroatoms selected from N, O,    and S, substituted with 0–3 R^(6e);-   R^(6b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0–3 R^(6e), C₂₋₈ alkenyl substituted with 0–3    R^(6e), C₂₋₈ alkynyl substituted with 0–3 R^(6e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0–2 R^(6e), and a (CH₂)_(r)-5–6    membered heterocyclic system containing 1–4 heteroatoms selected    from N, O, and S, substituted with 0–3 R^(6e);-   R^(6d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0–3 R^(6e), C₃₋₆ alkenyl    substituted with 0–3 R^(6e), C₃₋₆ alkynyl substituted with 0–3    R^(6e), a C₃₋₁₀ carbocyclic residue substituted with 0–3 R^(6e), and    a (CH₂)_(r)-5–6 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(6e);-   R^(6e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(6f)R^(6f), and (CH₂)_(r)phenyl;-   R^(6f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R^(6g) is selected from (CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(6d),    (CHR)_(q)S(O)_(p)R^(6d), (CHR)_(r)C(O)R^(6b),    (CHR)_(q)NR^(6a)R^(6a), (CHR)_(r)C(O)NR^(6a)R^(6a),    (CHR)_(r)C(O)NR^(6a)OR^(6d), (CHR)_(q)SO₂NR^(6a)R^(6a),    (CHR)_(r)C(O)OR^(6d), and a (CHR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0–5 R^(6e);-   R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(7d), (CRR)_(q)S(O)_(p)R^(7d),    (CRR)_(r)C(O)R^(7b), (CRR)_(r)NR^(7a)R^(7a),    (CRR)_(r)C(O)NR^(7a)R^(7a), (CRR)_(r)C(O)NR^(7a)OR^(7d),    (CRR)_(q)SO₂NR^(7a)R^(7a), (CRR)_(r)C(O)OR^(7d), a (CRR)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0–5 R^(7e), and a    (CRR)_(r)-5–10 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(7e);-   R^(7a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0–3 R^(7e), C₃₋₈ alkenyl    substituted with 0–3 R^(7e), C₃₋₈ alkynyl substituted with 0–3    R^(7e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0–5 R^(7e), and a (CH₂)_(r)-5–10 membered    heterocyclic system containing 1–4 heteroatoms selected from N, O,    and S, substituted with 0–3 R^(7e);-   R^(7b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0–3 R^(7e), C₂₋₈ alkenyl substituted with 0–3    R^(7e), C₂₋₈ alkynyl substituted with 0–3 R^(7e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0–2 R^(7e), and a (CH₂)_(r)-5–6    membered heterocyclic system containing 1–4 heteroatoms selected    from N, O, and S, substituted with 0–3 R^(7e);-   R^(7d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0–3 R^(7e), C₃₋₆ alkenyl    substituted with 0–3 R^(7e), C₃₋₆ alkynyl substituted with 0–3    R^(7e), a C₃₋₁₀ carbocyclic residue substituted with 0–3 R^(7e), and    a (CH₂)_(r)-5–6 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(7e);-   R^(7e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and (CH₂)_(r)phenyl;-   R^(7f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R⁸ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(8d), (CRR)_(r)S(O)_(p)R^(8d),    (CRR)_(r)C(O)R^(8b), (CRR)_(r)NR^(8a)R^(8a),    (CRR)_(r)C(O)NR^(8a)R^(8a), (CRR)_(r)C(O)NR^(8a)OR^(8d),    (CRR)_(r)SO₂NR^(8a)R^(8a), (CRR)_(r)C(O)OR^(8d), a (CRR)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0–5 R^(8e), and a    (CRR)_(r)-5–10 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(8e);-   alternatively, R⁸ and R⁹ join to form a C₃₋₆ cycloalkyl substituted    with 0–2 R^(8g) a 5–6 memebered ring lactam substituted with 0–2    R^(8g), or a 5–6 membered ring lactone substituted with 0–2 R^(8g);-   R^(8a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0–3 R^(8e), C₃₋₈ alkenyl    substituted with 0–3 R^(8e), C₃₋₈ alkynyl substituted with 0–3    R^(8e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0–5 R^(8e), and a (CH₂)_(r)-5–10 membered    heterocyclic system containing 1–4 heteroatoms selected from N, O,    and S, substituted with 0–3 R^(8e);-   R^(8b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0–3 R^(8e), C₂₋₈ alkenyl substituted with 0–3    R^(8e), C₂₋₈ alkynyl substituted with 0–3 R^(8e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0–2 R^(8e), and a (CH₂)_(r)-5–6    membered heterocyclic system containing 1–4 heteroatoms selected    from N, O, and S, substituted with 0–3 R^(8e);-   R^(8d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0–3 R^(8e), C₃₋₆ alkenyl    substituted with 0–3 R^(8e), C₃₋₆ alkynyl substituted with 0–3    R^(8e), a C₃₋₁₀ carbocyclic residue substituted with 0–3 R^(8e), and    a (CH₂)_(r)-5–6 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(8e);-   R^(8e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(8f)R^(8f), and (CH₂)_(r)phenyl;-   R^(8f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R^(8g) is selected from (CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(8d),    (CHR)_(q)S(O)_(p)R^(8d), (CHR)_(r)C(O)R^(8b),    (CHR)_(q)NR^(8a)R^(8a), (CHR)_(r)C(O)NR^(8a)R^(8a),    (CHR)_(r)C(O)NR^(8a)OR^(8d), (CHR)_(q)SO₂NR^(8a)R^(8a),    (CHR)_(r)C(O)OR^(8d), and a (CHR) r-C₃₋₁₀ carbocyclic residue    substituted with 0–5 R^(8e);-   R⁹ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(9d), (CRR)_(r)S(O)_(p)R^(9d),    (CRR)_(r)C(O)R^(9b), (CRR)_(r)NR^(9a)R^(9a),    (CRR)_(r)C(O)NR^(9a)R^(9a), (CRR)_(r)C(O)NR^(9a)OR^(9d),    (CRR)_(r)SO₂NR^(9a)R^(9a), (CRR)_(r)C(O)OR^(9d), a (CRR)_(r)—C₃₋₁₀    carbocyclic residue substituted with 0–5 R^(9e), and a    (CRR)_(r)-5–10 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(9e);-   R^(9a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0–3 R^(9e), C₃₋₈ alkenyl    substituted with 0–3 R^(9e), C₃₋₈ alkynyl substituted with 0–3    R^(9e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0–5 R^(9e), and a (CH₂)_(r)-5–10 membered    heterocyclic system containing 1–4 heteroatoms selected from N, O,    and S, substituted with 0–3 R^(9e);-   R^(9b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0–3 R^(9e), C₂₋₈ alkenyl substituted with 0–3    R^(9e), C₂₋₈ alkynyl substituted with 0–3 R^(9e), a (CH₂)_(r)—C₃₋₆    carbocyclic residue substituted with 0–2 R^(9e), and a (CH₂)_(r)-5–6    membered heterocyclic system containing 1–4 heteroatoms selected    from N, O, and S, substituted with 0–3 R^(9e);-   R^(9d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0–3 R^(9e), C₃₋₆ alkenyl    substituted with 0–3 R^(9e), C₃₋₆ alkynyl substituted with 0–3    R^(9e), a C₃₋₁₀ carbocyclic residue substituted with 0–3 R^(9e), and    a (CH₂)_(r)-5–6 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(9e);-   R^(9e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(9f)R^(9f), and (CH₂)_(r)phenyl;-   R^(9f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R¹⁰ is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(10d),    (CRR)_(r)S(O)_(p)R^(10d), (CRR)_(r)C(O)R^(10b),    (CRR)_(r)NR^(10a)R^(10a), (CRR)_(r)C(O)NR^(10a)R^(10a),    (CRR)_(r)C(O)NR^(10a)OR^(10d), (CRR)_(r)SO₂NR^(10a)R^(10a),    (CRR)_(r)C(O)OR^(10d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0–5 R^(10e), and a (CRR)_(r)-5–10 membered    heterocyclic system containing 1–4 heteroatoms selected from N, O,    and S, substituted with 0–3 R^(10e);-   alternatively, R¹⁰ and R¹¹ join to form a C₃₋₆ cycloalkyl    substituted with 0–2 R^(10g), a 5–6 membered ring lactam substituted    with 0–2 R^(10g), or a 5–6 membered ring lactone substituted with    0–2 R^(10g);-   R^(10a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0–3 R^(10e), C₃₋₈ alkenyl    substituted with 0–3 R^(10e), C₃₋₈ alkynyl substituted with 0–3    R^(10e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0–5 R^(10e), and a (CH₂)_(r)-5–10 membered    heterocyclic system containing 1–4 heteroatoms selected from N, O,    and S, substituted with 0–3 R^(10e);-   R^(10b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0–3 R^(10e), C₂₋₈ alkenyl substituted with    0–3 R^(10e), C₂₋₈ alkynyl substituted with 0–3 R^(10e), a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0–2 R^(10e), and    a (CH₂)_(r)-5–6 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(10e);-   R^(10d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0–3 R^(10e), C₃₋₆ alkenyl    substituted with 0–3 R^(10e), C₃₋₆ alkynyl substituted with 0–3    R^(10e), a C₃₋₁₀ carbocyclic residue substituted with 0–3 R^(10e),    and a (CH₂)_(r)-5–6 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(10e);-   R^(10e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OCl₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(10f)R^(10f), and (CH₂)_(r)phenyl;-   R^(10f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R^(10g) is selected from (CHR)_(q)OH, (CHR)_(q)SH,    (CHR)_(q)OR^(10d), (CHR)_(q)S(O)_(p)R^(10d), (CHR)_(r)C(O)R^(10b),    (CHR)_(q)NR^(10a)R^(10a), (CHR)_(r)C(O)NR^(10a)R^(10a),    (CHR)_(r)C(O)NR^(10a)OR^(10d),-   (CHR)_(q)SO₂NR^(10a)R^(10a), (CHR)_(r)C(O)OR^(10d), and a    (CHR)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0–5 R^(10e);-   R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(11d),    (CRR)_(r)S(O)_(p)R^(11d), (CRR)_(r)C(O)R^(11b),    (CRR)_(r)NR^(11a)R^(11a), (CRR)_(r)C(O)NR^(11a)R^(11a),    (CRR)_(r)C(O)NR^(11a)OR^(11d), (CRR)_(r)SO₂NR^(11a)R^(11a),    (CRR)_(r)C(O)OR^(11d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0–5 R^(11e), and a (CRR)_(r)-5–10 membered    heterocyclic system containing 1–4 heteroatoms selected from N, O,    and S, substituted with 0–3 R^(11e);-   R^(11a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0–3 R^(11e), C₃₋₈ alkenyl    substituted with 0–3 R^(11e), C₃₋₈ alkynyl substituted with 0–3    R^(11e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0–5 R^(11e), and a (CH₂)_(r)-5–10 membered    heterocyclic system containing 1–4 heteroatoms selected from N, O,    and S, substituted with 0–3 R^(11e);-   R^(11b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0–3 R^(11e), C₂₋₈ alkenyl substituted with    0–3 R^(11e), C₂₋₈ alkynyl substituted with 0–3 R^(11e), a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0–2 R^(11e), and    a (CH₂)_(r)-5–6 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(11e);-   R^(11d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0–3 R^(11e), C₃₋₆ alkenyl    substituted with 0–3 R^(11e), C₃₋₆ alkynyl substituted with 0–3    R^(11e), a C₃₋₁₀ carbocyclic residue substituted with 0–3 R^(11e),    and a (CH₂)_(r)-5–6 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(11e);-   R^(11e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f), and (CH₂)_(r)phenyl;-   R^(11f), at each occurrence, is independently selected from H, C₁₋₆    alkyl, and C₃₋₆ cycloalkyl;-   R¹² is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,    (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(12d),    (CRR)_(q)S(O)_(p)R^(12d), (CRR)_(r)C(O)R^(12b),    (CRR)_(r)NR^(12a)R^(12a), (CRR)_(r)C(O)NR^(12a)R^(12a),    (CRR)_(r)C(O)NR^(12a)OR^(12d), (CRR)_(q)SO₂NR^(12a)R^(12a),    (CRR)_(r)C(O)OR^(12d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0–5 R^(12e), and a (CRR)_(r)-5–10 membered    heterocyclic system containing 1–4 heteroatoms selected from N, O,    and S, substituted with 0–3 R^(12e);-   R^(12a), at each occurrence, is independently selected from H,    methyl, C₂₋₆ alkyl substituted with 0–3 R^(12e), C₃₋₈ alkenyl    substituted with 0–3 R^(12e), C₃₋₈ alkynyl substituted with 0–3    R^(12e), (CH₂)_(r)C₃₋₆ cycloalkyl, a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0–5 R^(12e), and a (CH₂)_(r)—S-10 membered    heterocyclic system containing 1–4 heteroatoms selected from N, O,    and S, substituted with 0–3 R^(12e);-   R^(12b), at each occurrence, is independently selected from C₁₋₆    alkyl substituted with 0–3 R^(12e), C₂₋₈ alkenyl substituted with    0–3 R^(12e), C₂₋₈ alkynyl substituted with 0–3 R^(12e), a    (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0–2 R^(12e), and    a (CH₂)_(r)-5–6 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(12e);-   R^(12d), at each occurrence, is independently selected from H,    methyl, —CF₃, C₂₋₆ alkyl substituted with 0–3 R^(12e), C₃₋₆ alkenyl    substituted with 0–3 R^(12e), C₃₋₆ alkynyl substituted with 0–3    R^(12e), a C₃₋₁₀ carbocyclic residue substituted with 0–3 R^(12e),    and a (CH₂)_(r)-5–6 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–3 R^(12e);-   R^(12e), at each occurrence, is independently selected from C₁₋₆    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I,    CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₆ alkyl, SH,    (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(12f)R^(12f), and (CH₂)_(r)phenyl;-   R^(12f), at each occurrence, is selected from H, C₁₋₆ alkyl, and    C₃₋₆ cycloalkyl;-   R¹⁴ and R^(14a) are independently selected from H, and C₁₋₄alkyl    substituted with 0–1 R^(14b), and F;-   alternatively, R¹⁴ and R^(14a) can join to form a C₃₋₆ cycloalkyl;-   R^(14b), at each occurrence, is independently selected from —OH,    —SH, —NR^(14c)R^(14c), —C(O)NR^(14c)R^(14c), —NHC(O)R^(14c) and    phenyl;-   R^(14c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R¹⁶ is selected from H, C₁₋₄ alkyl substituted with 0–3 R^(16a), and    C₃₋₆ cycloalkyl substituted with 0–3 R^(16a);-   R^(16a) is selected from C₁₋₄ alkyl, —OH, —SH, —NR^(16c)R^(16c),    —C(O)NR^(16c)R^(16c), and —NHC(O)R^(16c);-   R^(16c) is selected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl;-   R¹⁷ is selected from H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl;-   R¹⁸ is selected from H, C₁₋₄ alkyl, and C₃₋₄ cycloalkyl;-   n is selected from 0, 1, and 2;-   l is selected from 0 and 1;-   m is selected from 0 and 1;-   p, at each occurrence, is selected from 0, 1, or 2;-   q, at each occurrence, is selected from 1, 2, 3, or 4; and-   r, at each occurrence, is selected from 0, 1, 2, 3, or 4.

In another embodiment, the present invention is directed to compounds offormula (I) wherein

-   R¹⁴ and R^(14a) are independently selected from H, and C₁₋₄alkyl    substituted with 0–1 R^(14b),-   alternatively, R¹⁴ and R^(14a) can join to form a C₃₋₆ cycloalkyl.

[3] Thus, in a another embodiment, the present invention provides novelcompounds of formula (I):

-   R¹⁶ is selected from H, C₁₋₄ alkyl substituted with 0–1 R^(16a),    wherein the alkyl is selected from methyl, ethyl, propyl, i-propyl,    butyl, i-butyl, and s-butyl, and C₃₋₄ cycloalkyl substituted with    0–3 R^(16a) wherein the cycloalkyl is selected from cyclopropyl and    cyclobutyl;-   R^(16a) is selected from methyl, ethyl, propyl, i-propyl, —OH, —SH,    —NR^(16c)R^(16c), —C(O)NR^(16c)R^(16c), and —NHC(O)R^(16c);-   R^(16c) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    cyclopropyl, cyclopentyl, and cyclohexyl; and-   R¹⁷ is selected from H, methyl, ethyl, propyl, and i-propyl.

[4] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   R⁹ and R¹¹ are H; and-   R⁸ and R¹⁰ are independently selected from H, methyl, ethyl, propyl,    i-propyl, butyl, and cyclopropyl.

[5] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   R³ is selected from (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(3d),    (CRR)_(q)S(O)_(p)R^(3d), (CRR)_(r)C(O)R^(3b),    (CRR)_(q)NR^(3a)R^(3a), (CRR)_(r)C(O)NR^(3a)R^(3a),    (CRR)_(r)C(O)NR^(3a)OR^(3d), (CRR)_(q)SO₂NR^(3a)R^(3a),    (CRR)_(r)C(O)OR^(3d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0–5 R^(3e), and a (CRR)_(r)-5–10 membered    heterocyclic system containing 1–4 heteroatoms selected from N, O,    and S, substituted with 0–3 R^(3e) wherein the heterocyclic system    is selected from pyridinyl, thiophenyl, furanyl, indazolyl,    benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl,    benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl,    indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl,    piperidinyl, pyrrazolyl, pyrrolidinyl, tetrahydrofuranyl,    tetrahydrothiophenyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,    thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl;-   R⁶ is selected from H, (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(6d),    (CRR)_(q)S(O)_(p)R^(6d), (CRR)_(r)C(O)R^(6b),    (CRR)_(q)NR^(6a)R^(6a), (CRR)_(r)C(O)NR^(6a)R^(6a),    (CRR)_(r)C(O)NR^(6a)OR^(6d), (CRR)_(q)SO₂NR^(6a)R^(6a),    (CRR)_(r)C(O)OR^(6d), a (CRR)_(r)—C₆₋₁₀ carbocyclic residue    substituted with 0–5 R^(6e), and a (CRR)_(r)-5–10 membered    heterocyclic system containing 1–4 heteroatoms selected from N, O,    and S, substituted with 0–6 R^(6e) wherein the heterocyclic system    is selected from pyridinyl, thiophenyl, furanyl, indazolyl,    benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl,    benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl,    indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl,    piperidinyl, pyrrazolyl, pyrrolidinyl, tetrahydrofuranyl,    tetrahydrothiophenyl, 1,2,4-triazolyl, 1,2,6-triazolyl, tetrazolyl,    thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl;-   R⁷ is H;-   R¹² is selected from H, methyl, ethyl, and propyl;-   alternatively, R³ and R¹² join to form a C₃₋₆ cycloalkyl substituted    with 0–2 R^(3g), a 5–6 membered lactam ring substituted with 0–2    R^(3g), or a 5–6 membered lactone ring substituted with 0–2 R^(3g);    and-   m+1 is equal to 0 or 1.

[6] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   R¹ is selected from phenyl substituted with 0–3 R⁴ and a 5–10    membered heteroaryl system substituted with 0–3 R⁴, wherein the    heteroaryl is selected from benzimidazolyl, benzofuranyl,    benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,    benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,    cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl    isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,    pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl,    quinolinyl, thiazolyl, thienyl, and tetrazolyl;-   R² is selected from phenyl substituted with 0–3 R⁵ and a 5–10    membered heteroaryl system containing 1–4 heteroatoms substituted    with 0–3 R⁵, wherein the heteroaryl system is selected from    benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl,    benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,    benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl,    indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolinyl,    isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl,    pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl,    and tetrazolyl.

[7] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   R⁴, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl,    C₂₋₈ alkynyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(4a)R^(4a), (CR′R′)_(r)OH, (CR′R′)_(r)OR^(4d),    (CR′R′)_(r)SH, (CR′R′)_(r)SR^(4d), (CR′R′)_(r)C(O)OH,    (CR′R′)_(r)C(O)R^(4b), (CR′R′)_(r)C(O)NR^(4a)R^(4a),    (CR′R′)_(r)NR^(4f)C(O)R^(4b), (CR′R′)_(r)C(O)OR^(4d),    (CR′R′)_(r)OC(O)R^(4b), (CR′R′)_(r)NR^(4f)C(O)OR^(4d),    (CR′R′)_(r)OC(O)NR^(4a)R^(4a), (CR′R′)_(r)NR^(4a)C(O)NR^(4a)R^(4a),    (CR′R′)_(r)S(O)_(p)R^(4b), (CR′R′)_(r)S(O)₂NR^(4a)R^(4a),    (CR′R′)_(r)NR^(4f)S(O)₂R^(4b), (CR′R′)_(r)NR^(4f)S(O)₂    NR^(4a)R^(4a), C₁₋₆ haloalkyl, and (CR′R′)_(r)phenyl substituted    with 0–3 R^(4e);-   alternatively, two R⁴ on adjacent atoms join to form —O—(CH₂)—O—;-   R^(4a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl,    pentyl, hexyl, allyl, propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic    residue selected from cyclopropyl, cyclobutyl, cyclopentyl and    cyclohexyl;-   R^(4b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl, allyl,    propargyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0–3    R^(4e), wherein the carbocyclic residue is selected from    cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and a    (CH₂)_(r)-5–6 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–2 R^(4e),    wherein the heterocyclic system is selected from pyridinyl,    thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,    benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,    quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl,    isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl,    1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl,    thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl;-   R^(4d), at each occurrence, is selected from H, methyl, CF₃, ethyl,    propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl,    allyl, propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue selected    from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;-   R^(4e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;-   R^(4f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, and cyclopropyl, cyclobutyl, and phenyl;-   R⁵, at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, i-butyl, s-butyl, t-butyl, pentyl, hexyl,    (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(5a)R^(5a), (CR′R′)_(r)OH, (CR′R′)_(r)OR^(5d),    (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)SR^(5d),    (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)R^(5b),    (CR′R′)_(r)C(O)NR^(5a)R^(5a), (CR′R′)_(r)NR^(5f)C(O)R^(5b),    (CR′R′)_(r)C(O)OR^(5d), (CR′R′)_(r)OC(O)R^(5b),    (CR′R′)_(r)NR^(5f)C(O)OR^(5d), (CR′R′)_(r)OC(O)NR^(5a)R^(5a),    (CR′R′)_(r)NR^(5a)C(O)NR^(5a)R^(5a),    (CR′R′)_(r)NR^(7a)C(O)NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7a)C(O)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)S(O)_(p)R^(5b),    (CR′R′)_(r)S(O)₂NR^(5a)R^(5a), (CR′R′)_(r)NR^(5f)S(O)₂R^(5b), C₁₋₆    haloalkyl, and (CHR′)_(r)phenyl substituted with 0–3 R^(5e), a    (CRR)_(r)-5–10 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–2 R^(5c),

-   alternatively, two R⁵ on adjacent atoms join to form —O—(CH₂)—O—;-   R^(5a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl,    pentyl, hexyl, allyl, propargyl, and a (CH₂)_(r)—C₃₋₁₀ carbocyclic    residue substituted with 0–1 R^(5e), wherein the carbocyclic residue    is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,    phenyl and naphthyl;-   R^(5b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl, allyl,    propargyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue selected from    cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl; and a    (CH₂)_(r)-5–6 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, wherein the heterocyclic    system is selected from pyridinyl, thiophenyl, furanyl, indazolyl,    azetidinyl, benzothiazolyl, benzimidazolyl, benzothiophenyl,    benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,    isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl,    isothiadiazolyl, isoxazolyl, morphlinyl, piperidinyl, pyrrolyl,    2,5-dihydropyrrolyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,    tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and    pyrimidinyl;-   R^(5d), at each occurrence, is selected from H, methyl, CF₃, ethyl,    propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl,    allyl, propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue selected    from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;-   R^(5e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl; and-   R^(5f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, and cyclopropyl, cyclobutyl, and phenyl.

[8] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   R⁵ is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl,    s-butyl, pentyl, hexyl, CF₃, CF₂CF₃, CF₂H, OCF₃, Cl, Br, I, F, SCF₃,    NR^(5a)R^(5a), NHC(O)OR^(5a), NHC(O)R^(5b), and NHC(O)NHR^(5a); and-   R¹² is selected from H and methyl.

[9] In another embodiment, the present invention provides novelcompounds of formula (I), wherein:

-   X is —CHR¹⁶NR¹⁷—;-   R¹ is selected from phenyl substituted with 0–3 R⁴, and a 5–10    membered heteroaryl system substituted with 0–2 R⁴, wherein the    heteroaryl is selected from indolyl, and pyridyl;-   R² is phenyl substituted with 0–2 R⁵;-   R³ is selected from (CRR)_(q)OH, (CRR)_(q)OR^(3d), (CH₂)_(r)C(O)OH,    (CH₂)_(r)C(O)NR^(3a)R^(3a), (CHR)_(r)C(O)NR^(3a)OR^(3d),    (CH₂)C(O)R^(3b), (CH₂)_(r)C(O)OR^(3d), and (CH₂)-phenyl;-   R^(3a) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, s-butyl, t-butyl, allyl, CH₂CF₃, C(CH₃)CH₂CH₂OH,    cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl,    cyclohexyl, phenyl, and benzyl;-   R^(3b) is selected from pyrrolidinyl, pyrrolid-3-enyl, and    morpholinyl;-   R^(3d) is selected from methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, t-butyl and benzyl;-   R is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    i-butyl, s-butyl, pentyl, neopentyl, phenyl and benzyl;-   R⁴ is selected from methyl, ethyl, propyl, i-propyl, butyl,    ethylene, OCH₃, OCF₃, SCH₃, SO₂CH₃, Cl, F, Br, CN;-   alternatively, two R⁴ join to form —O—(CH₂)—O—;-   R⁶ is selected from H, methyl, ethyl, propyl, i-propyl, butyl,    C(O)OCH₃, C(O)NHCH₂CH₃;-   R⁷ is H;-   R¹⁶ is selected from H and methyl;-   R¹⁷ is selected from H and methyl;-   m is 0-   l is 0-   r is 0 or 1; and-   q is 1.

[10] In another embodiment, the present invention provides novelcompounds of formula (I), wherein the compound is selected from thecompounds of Table 1.

In another embodiment, the present invention is directed to apharmaceutical composition, comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method formodulation of chemokine or chemokine receptor activity comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of Formula (I).

In another embodiment, the present invention is directed to a method formodulation of CCR-2 receptor activity comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof Formula (I).

In another embodiment, the present invention is directed to a method formodulation of MCP-1, MCP-2, MCP-3 and MCP-4, and MCP-5 activity that ismediated by the CCR2 receptor comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method formodulation of MCP-1 activity comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method fortreating disorders, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula (I),said disorders being selected from osteoarthritis, aneurism, fever,cardiovascular effects, Crohn's disease, congestive heart failure,autoimmune diseases, HIV-infection, HIV-associated dementia, psoriasis,idiopathic pulmonary fibrosis, transplant arteriosclerosis, physically-or chemically-induced brain trauma, inflammatory bowel disease,alveolitis, colitis, systemic lupus erythematosus, nephrotoxic serumnephritis, glomerularnephritis, asthma, multiple sclerosis,artherosclerosis, rheumatoid arthritis, restinosis, organtransplantation, and cancer.

In another embodiment, the present invention is directed to a method fortreating disorders, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula (I),wherein said disorders being selected from psoriasis, idiopathicpulmonary fibrosis, transplant arteriosclerosis, physically- orchemically-induced brain trauma, inflammatory bowel disease, alveolitis,colitis, systemic lupus erythematosus, nephrotoxic serum nephritis,glomerularnephritis, asthma, multiple sclerosis, artherosclerosis, andrheumatoid arthritis, restinosis, organ transplantation, and cancer.

In another embodiment, the present invention is directed to a method fortreating disorders, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula (I),wherein said disorders being selected from alveolitis, colitis, systemiclupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis,asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis,restinosis, organ transplantation, and cancer.

In another embodiment, the present invention is directed to a method fortreating disorders, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula (I),wherein said disorders being selected from asthma, multiple sclerosis,artherosclerosis, and rheumatoid arthritis.

In another embodiment, the present invention is directed to a method fortreating disorders, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula (I),wherein said disorders being selected from restinosis, organtransplantation, and cancer.

In another embodiment, the present invention is directed to a method fortreating rheumatoid arthritis, comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method fortreating multiple sclerosis, comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method fortreating atherosclerosis, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula (I).

In another embodiment, the present invention is directed to a method fortreating asthma, comprising administering to a patient in need thereof atherapeutically effective amount of a compound of Formula (I).

In another embodiment, the present invention is directed to a method fortreating restinosis, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of Formula (I).

In another embodiment, the present invention is directed to a method fortreating organ transplantation, comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method fortreating cancer, comprising administering to a patient in need thereof atherapeutically effective amount of a compound of Formula (I).

In another embodiment, the present invention is directed to a method fortreating inflammatory diseases, comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed to a method fortreating inflammatory diseases which are at least partially mediated byCCR-2, comprising administering to a patient in need thereof atherapeutically effective amount of a compound of Formula (I).

In another embodiment, the present invention is directed to a method formodulation of CCR2 activity comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of Formula(I).

In another embodiment, the present invention is directed the use of acompound of Formula (I) in the preparation of a medicament for thetreatment of osteoarthritis, aneurism, fever, cardiovascular effects,Crohn's disease, congestive heart failure, autoimmune diseases,HIV-infection, HIV-associated dementia, psoriasis, idiopathic pulmonaryfibrosis, transplant arteriosclerosis, physically- or chemically-inducedbrain trauma, inflammatory bowel disease, alveolitis, colitis, systemiclupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis,asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.

In another embodiment, the present invention is directed to a compoundof formula (I) for use in therapy.

In another embodiment, X is —CHR¹⁶NR¹⁷—; and

-   R¹⁶ is selected from H, C₁₋₄ alkyl substituted with 0–1 R^(16a),    wherein the alkyl is selected from methyl, ethyl, propyl, i-propyl,    butyl, i-butyl, and s-butyl, and C₃₋₄ cycloalkyl substituted with    0–3 R^(16a) wherein the cycloalkyl is selected from cyclopropyl and    cyclobutyl;-   R^(16a) is selected from methyl, ethyl, propyl, i-propyl, —OH, —SH,    NR^(16c)R^(16c), —C(O)NR^(16c)R^(16c), and —NHC(O)R^(16c); and-   R¹⁷ is selected from H, methyl, ethyl, propyl, and i-propyl.-   In another embodiment, R⁷, R⁸, R⁹, and R¹¹ are H;-   R¹⁰ is selected from H and methyl;-   R¹⁶ is selected from H and methyl;-   R¹⁷ is selected from H and methyl;-   m is 0 or 1; and-   l is 0 or 1.-   In another embodiment, R³ is selected from (CRR)_(q)OH, (CRR)_(q)SH,    (CRR)_(q)OR^(3d), (CRR)_(q)S(O)_(p)R^(3d), (CRR)_(r)C(O)R^(3b),    (CRR)_(q)NR^(3a)R^(3a), (CRR)_(r)C(O)NR^(3a)R^(3a),    (CRR)_(r)C(O)NR^(3a)OR^(3d), (CRR)_(q)SO₂NR^(3a)R^(3a),    (CRR)_(r)C(O)OR^(3d), a (CRR)_(r)—C₃₋₁₀ carbocyclic residue    substituted with 0–5 R^(3e), and a (CRR)_(r)-5–10 membered    heterocyclic system containing 1–4 heteroatoms selected from N, O,    and S, substituted with 0–3 R^(3e) wherein the heterocyclic system    is selected from pyridinyl, thiophenyl, furanyl, indazolyl,    benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl,    benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl,    indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl,    piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,    tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and    pyrimidinyl;-   alternatively, R³ and R¹² join to form a C₃₋₆ cycloalkyl substituted    with 0–2 R^(3g), a C₅₋₆ lactam substituted with 0–2 R^(3g), or a    C₅₋₆ lactone substituted with 0–2 R^(3g).-   In another embodiment, R³ is selected from (CRR)_(q)OH,    (CH₂)_(r)C(O)OH, (CH₂)_(r)C(O)NR^(3a)R^(3a),    (CHR)_(r)C(O)NR^(3a)OR^(3d), (CH₂)C(O)R^(3b), (CH₂)_(r)C(O)OR^(3d),    and (CH₂)-phenyl.-   In another embodiment, R³ is H and R⁶, is selected from C₁₋₆ alkyl,    C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CRR)_(q)OH, (CRR)_(q)SH,    (CRR)_(q)OR^(6d), (CRR)_(q)S(O)_(p)R^(6d), (CRR)_(r)C(O)R^(6b),    (CRR)_(r)NR^(6a)R^(6a), (CRR)_(r)C(O)NR^(6a)R^(6a),    (CRR)_(r)C(O)NR^(6a)OR^(6d), (CRR)SO₂NR^(6a)R^(6a),    (CRR)_(r)C(O)OR^(6d), a (CRR) r-C₃₋₁₀ carbocyclic residue    substituted with 0–5 R^(6e), and a (CRR)_(r)-5–10 membered    heterocyclic system containing 1–4 heteroatoms selected from N, O,    and S, substituted with 0–3 R^(6e).-   In another embodiment, R⁶ is selected from H, (CRR)_(q)OH,    (CRR)_(q)SH, (CRR)_(q)OR^(6d), (CRR)_(q)S(O)_(p)R^(6d),    (CRR)_(r)C(O)R^(6b), (CRR)_(q)NR^(6a)R^(6a),    (CRR)_(r)C(O)NR^(6a)R^(6a), (CRR)_(r)C(O)NR^(6a)OR^(6d),    (CRR)_(q)SO₂NR^(6a)R^(6a), (CRR)_(r)C(O)OR^(6d), a (CRR) r-C₆₋₁₀    carbocyclic residue substituted with 0–5 R^(6e), and a    (CRR)_(r)-5–10 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–6 R^(6e)    wherein the heterocyclic system is selected from pyridinyl,    thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,    benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,    quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl,    isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl,    1,2,4-triazolyl, 1,2,6-triazolyl, tetrazolyl, thiadiazolyl,    thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.-   In another embodiment, R¹ is selected from phenyl substituted with    0–3 R⁴ and a 5–10 membered heteroaryl system substituted with 0–3    R⁴, wherein the heteroaryl is selected from benzimidazolyl,    benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl,    benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,    benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl,    indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl,    pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl, pyrimidinyl,    pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, and    tetrazolyl.-   In another embodiment, R¹ is selected from phenyl substituted with    0–2 R⁴, indolyl, and pyridyl.-   In another embodiment, R² is selected from phenyl substituted with    0–3 R⁵ and a 5–10 membered heteroaryl system containing 1–4    heteroatoms substituted with 0–3 R⁵, wherein the heteroaryl system    is selected from benzimidazolyl, benzofuranyl, benzothiofuranyl,    benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl,    benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, cinnolinyl,    furanyl, imidazolyl, indazolyl, indolyl, isoquinolinyl isothiazolyl,    isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,    pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl,    thiazolyl, thienyl, and tetrazolyl.-   In another embodiment, R² is phenyl substituted with 0–2 R⁵.-   In another embodiment, R⁴, at each occurrence, is selected from C₁₋₈    alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl,    Br, I, F, NO₂, CN, (CR′R′)_(r)NR^(4a)R^(4a), (CR′R′)_(r)OH,    (CR′R′)_(r)OR^(4d), (CR′R′)_(r)SH, (CR′R′)_(r)SR^(4d),    (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)R^(4b),    (CR′R′)_(r)C(O)NR^(4a)R^(4a), (CR′R′)_(r)NR^(4f)C(O)R^(4b),    (CR′R′)_(r)C(O)OR^(4d), (CR′R′)_(r)OC(O)R^(4b),    (CR′R′)_(r)NR^(4f)C(O)OR^(4d), (CR′R′)_(r)OC(O)NR^(4a)R^(4a),    (CR′R′)_(r)NR^(4a)C(O)NR^(4a)R^(4a), (CR′R′)_(r)S(O)_(p)R^(4b),    (CR′R′)_(r)S(O)₂NR^(4a)R^(4a), (CR′R′)_(r)NR^(4f)S(O)₂R^(4b),    (CR′R′)_(r)NR^(4f)S(O)₂ NR^(4a)R^(4a), C₁₋₆ haloalkyl, and    (CR′R′)_(r)phenyl substituted with 0–3 R^(4e);-   alternatively, two R⁴ on adjacent atoms join to form —O—(CH₂)—O—;-   R^(4a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl,    pentyl, hexyl, allyl, propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic    residue selected from cyclopropyl, cyclobutyl, cyclopentyl and    cyclohexyl;-   R^(4b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl, allyl,    propargyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0–3    R^(4e), wherein the carbocyclic residue is selected from    cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, and a    (CH₂)_(r)-5–6 membered heterocyclic system containing 1–4    heteroatoms selected from N, O, and S, substituted with 0–2 R^(4e),    wherein the heterocyclic system is selected from pyridinyl,    thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,    benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl,    quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl,    isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl,    1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl,    thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl;-   R^(4d), at each occurrence, is selected from H, methyl, CF₃, ethyl,    propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl,    allyl, propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue selected    from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;-   R^(4e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl;-   R^(4f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, and cyclopropyl, cyclobutyl, and phenyl.-   In another embodiment, R⁴ is selected from methyl, ethyl, propyl,    i-propyl, butyl, ethylene, OCH₃, OCF₃, SCH₃, SO₂CH₃, Cl, F, Br, and    CN;-   alternatively, two R⁴ join to form —O—(CH₂)—O—.-   In another embodiment, R⁵, at each occurrence, is selected from    methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl,    pentyl, hexyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,    (CR′R′)_(r)NR^(5a)R^(5a), (CR′R′)_(r)OH, (CR′R′)_(r)OR^(5d),    (CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)SR^(5d),    (CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)R^(5b),    (CR′R′)_(r)C(O)NR^(5a)R^(5a), (CR′R′)_(r)NR^(5f)C(O)R^(5b),    (CR′R′)_(r)C(O)OR^(5d), (CR′R′)_(r)OC(O)R^(5b),    (CR′R′)_(r)NR^(5f)C(O)OR^(5d), (CR′R′)_(r)OC(O)NR^(5a)R^(5a),    (CR′R′)_(r)NR^(5a)C(O)NR^(5a)R^(5a),    (CR′R′)_(r)NR^(7a)C(O)NR^(7a)R^(7a),    (CR′R′)_(r)NR^(7a)C(O)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)S(O)_(p)R^(5b),    (CR′R′)_(r)S(O)₂NR^(5a)R^(5a), (CR′R′)_(r)NR^(5f)S(O)₂R^(5b), C₁₋₆    haloalkyl, and (CHR′)_(r)phenyl substituted with 0–3 R^(5e);-   alternatively, two R⁵ on adjacent atoms join to form —O—(CH₂)—O—;-   R^(5a), at each occurrence, is independently selected from H,    methyl, ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl,    pentyl, hexyl, allyl, propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic    residue selected from cyclopropyl, cyclobutyl, cyclopentyl and    cyclohexyl;-   R^(5b), at each occurrence, is selected from methyl, ethyl, propyl,    i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl, allyl,    propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue selected from    cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;-   R^(5d), at each occurrence, is selected from H, methyl, CF₃, ethyl,    propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl,    allyl, propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue selected    from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;-   R^(5e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈    alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,    NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅    alkyl, (CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl; and-   R^(5f), at each occurrence, is selected from H, methyl, ethyl,    propyl, i-propyl, butyl, and cyclopropyl, cyclobutyl, and phenyl.

In another embodiment, R⁵ is selected from methyl, ethyl, propyl,i-propyl, butyl, i-butyl, s-butyl, pentyl, hexyl, CF₃, CF₂CF₃, CF₂H,OCF₃, Cl, Br, I, F, SCF₃, NR^(5a)R^(5a), NHC(O)OR^(5a), NHC(O)R^(5b),and NHC(O)NHR^(5a).

In another embodiment, Z is a bond and R² is a 5–10 membered heteroarylsystem containing 1–4 heteroatoms selected from N, O, and S, substitutedwith 0–3 R⁷ wherein the heteroaryl is selected from indolyl,benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalonyl, cinnolinyl, furanyl, imidazolyl,indazolyl, indolyl, isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl,phthalazinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyridinyl,pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, thiazolyl, thienyl, andtetrazolyl.

In another embodiment, the compound is of the formula (Ia)

and R² is phenyl substituted with 0–3 R⁷.

In another embodiment, the compound is of formula (Ib)

and R² is a 5–10 membered heteroaryl system containing 1–4 heteroatomsselected from N, O, and S, substituted with 0–3 R⁷ wherein theheteroaryl is selected from indolyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl, isoquinolinylisothiazolyl, isoxazolyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl,quinolinyl, thiazolyl, thienyl, and tetrazolyl.In another embodiment, the present invention is directed to a compoundof formula (I) wherein

-   Z is selected from a bond and —C(O)NH;-   X is —CH₂NH—;-   R^(a) is H;-   R⁷, R⁸, R⁹, and R¹¹ are H;-   R¹⁰ is selected from H and methyl;-   R¹⁴ and R^(14a) are independently selected from H, methyl, and F;-   alternatively, R¹⁴ and R^(14a) can join to form a C₃₋₆ cycloalkyl;-   R¹⁶ is selected from H and methyl; and-   R¹⁷ is selected from H and methyl.

In another embodiment, the present invention is directed the use of acompound of Formula (I) in the preparation of a medicament for thetreatment of osteoarthritis, aneurism, fever, cardiovascular effects,Crohn's disease, congestive heart failure, autoimmune diseases,HIV-infection, HIV-associated dementia, psoriasis, idiopathic pulmonaryfibrosis, transplant arteriosclerosis, physically- or chemically-inducedbrain trauma, inflammatory bowel disease, alveolitis, colitis, systemiclupus erythematosus, nephrotoxic serum nephritis, glomerularnephritis,asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.

In another embodiment, the present invention is directed to a compoundof formula (I) for use in therapy.

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This invention alsoencompasses all combinations of preferred aspects of the invention notedherein. It is understood that any and all embodiments of the presentinvention may be taken in conjunction with any other embodiment todescribe additional even more preferred embodiments of the presentinvention. Furthermore, any elements of an embodiment are meant to becombined with any and all other elements from any of the embodiments todescribe additional embodiments.

DEFINITIONS

The compounds herein described may have asymmetric centers. Compounds ofthe present invention containing an asymmetrically substituted atom maybe isolated in optically active or racemic forms. It is well known inthe art how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis from optically active starting materials.Many geometric isomers of olefins, C═N double bonds, and the like canalso be present in the compounds described herein, and all such stableisomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. All chiral, diastereomeric, racemic forms and allgeometric isomeric forms of a structure are intended, unless thespecific stereochemistry or isomeric form is specifically indicated.

One enantiomer of a compound of Formula I may display superior activitycompared with the other. Thus, all of the stereochemistries areconsidered to be a part of the present invention. When required,separation of the racemic material can be achieved by HPLC using achiral column or by a resolution using a resolving agent such ascamphonic chloride as in Steven D. Young, et al, Antimicrobial Agentsand Chemotheraphy, 1995, 2602–2605.

The term “substituted,” as used herein, means that any one or morehydrogens on the designated atom or ring is replaced with a selectionfrom the indicated group, provided that the designated atom's or ringatom's normal valency is not exceeded, and that the substitution resultsin a stable compound. When a substitent is keto (i.e., ═O), then 2hydrogens on the atom are replaced.

When any variable (e.g., R¹⁰) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0–2 R¹⁰, then saidgroup may optionally be substituted with up to two R¹⁰ groups and R¹⁰ ateach occurrence is selected independently from the definition of R¹⁰.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

As used herein, “C₁₋₈ alkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, examples of which include, but are notlimited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl. C₁₋₈ alkyl, is intended toinclude C₁, C₂, C₃, C₄, C₅, C₆, C₇, and C₈ alkyl groups. “Alkenyl” isintended to include hydrocarbon chains of either a straight or branchedconfiguration and one or more unsaturated carbon-carbon bonds which mayoccur in any stable point along the chain, such as ethenyl, propenyl,and the like. “Alkynyl” is intended to include hydrocarbon chains ofeither a straight or branched configuration and one or more unsaturatedtriple carbon-carbon bonds which may occur in any stable point along thechain, such as ethynyl, propynyl, and the like. “C₃₋₆ cycloalkyl” isintended to include saturated ring groups having the specified number ofcarbon atoms in the ring, including mono-, bi-, or poly-cyclic ringsystems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, andcycloheptyl in the case of C₇ cycloalkyl. C₃₋₆ cycloalkyl, is intendedto include C₃, C₄, C₅, and C₆ cycloalkyl groups

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo, andiodo; and “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, for example CF₃,having the specified number of carbon atoms, substituted with 1 or morehalogen (for example —C_(v)F_(w) where v=1 to 3 and w=1 to (2v+1)).

As used herein, the term “5–6-membered cyclic ketal” is intended to mean2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxane andtheir derivatives.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which maybe saturated, partially unsaturated, or aromatic. Examples of suchcarbocycles include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,;[3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane(decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl,adamantyl, or tetrahydronaphthyl(tetralin).

As used herein, the term “heterocycle” or “heterocyclic system” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated,partially unsaturated or unsaturated (aromatic), and which consists ofcarbon atoms and 1, 2, 3, or 4 heteroatoms independently selected fromthe group consisting of N, NH, O and S and including any bicyclic groupin which any of the above-defined heterocyclic rings is fused to abenzene ring. The nitrogen and sulfur heteroatoms may optionally beoxidized. The heterocyclic ring may be attached to its pendant group atany heteroatom or carbon atom which results in a stable structure. Theheterocyclic rings described herein may be substituted on carbon or on anitrogen atom if the resulting compound is stable. If specificallynoted, a nitrogen in the heterocycle may optionally be quaternized. Itis preferred that when the total number of S and O atoms in theheterocycle exceeds 1, then these heteroatoms are not adjacent to oneanother. As used herein, the term “aromatic heterocyclic system” or“heteroaryl” is intended to mean a stable 5- to 7-membered monocyclic orbicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring whichconsists of carbon atoms and from 1 to 4 heterotams independentlyselected from the group consisting of N, O and S and is aromatic innature.

Examples of heterocycles include, but are not limited to, 1H-indazole,2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 1H-indolyl,4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. In another aspect of theinvention, the heterocycles include, but are not limited to, pyridinyl,thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl,benzothiaphenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl, piperidonyl,4-piperidonyl, piperonyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl,tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl. Alsoincluded are fused ring and spiro compounds containing, for example, theabove heterocycles.

Examples of heteroaryls are 1H-indazole, 2H,6H-1,5,2-dithiazinyl,indolyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl,acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl,carbazolyl, 4aH-carbazolyl, β-carbolinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, indazolyl, indolenyl, indolinyl, indolizinyl,indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl,piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl,pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl, tetrazolyl, and xanthenyl. In another aspect of theinvention, examples of heteroaryls are indolyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzoxazolyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazalonyl, cinnolinyl, furanyl, imidazolyl, indazolyl, indolyl,isoquinolinyl isothiazolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridyl, pyridinyl, pyrimidinyl, pyrrolyl, quinazolinyl,quinolinyl, thiazolyl, thienyl, and tetrazolyl.

As used herein, the term “cyclic acetal” or or the phrase when twovariables “join to form a cyclic acetal” is intended to mean thesubstituent —O—CH₂—O—.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic residues such as amines; alkali or organic salts ofacidic residues such as carboxylic acids; and the like. Thepharmaceutically acceptable salts include the conventional non-toxicsalts or the quaternary ammonium salts of the parent compound formed,for example, from non-toxic inorganic or organic acids. For example,such conventional non-toxic salts include those derived from inorganicacids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like; and the salts prepared from organic acids such asacetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric,citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.,1985, p. 1418, the disclosure of which is hereby incorporated byreference.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc .. . ) the compounds of the present invention may be delivered in prodrugform. Thus, the present invention is intended to cover prodrugs of thepresently claimed compounds, methods of delivering the same andcompositions containing the same. “Prodrugs” are intended to include anycovalently bonded carriers which release an active parent drug of thepresent invention in vivo when such prodrug is administered to amammalian subject. Prodrugs the present invention are prepared bymodifying functional groups present in the compound in such a way thatthe modifications are cleaved, either in routine manipulation or invivo, to the parent compound. Prodrugs include compounds of the presentinvention wherein a hydroxy, amino, or sulfhydryl group is bonded to anygroup that, when the prodrug of the present invention is administered toa mammalian subject, it cleaves to form a free hydroxyl, free amino, orfree sulfhydryl group, respectively. Examples of prodrugs include, butare not limited to, acetate, formate and benzoate derivatives of alcoholand amine functional groups in the compounds of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended toembody stable compounds.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention alone or an amount of the combinationof compounds claimed or an amount of a compound of the present inventionin combination with other active ingredients effective to inhibit MCP-1or effective to treat or prevent inflammatory disorders.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

SYNTHESIS

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. The reactions areperformed in solvents appropriate to the reagents and materials employedand are suitable for the transformations being effected. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and work up procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. It is understood by one skilled in the art oforganic synthesis that the functionality present on various portions ofthe molecule must be compatible with the reagents and reactionsproposed. Such restrictions to the substituents which are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used. This will sometimesrequire a judgment to modify the order of the synthetic steps or toselect one particular process scheme over another in order to obtain adesired compound of the invention. It will also be recognized thatanother major consideration in the planning of any synthetic route inthis field is the judicious choice of the protecting group used forprotection of the reactive functional groups present in the compoundsdescribed in this invention. An authoritative account describing themany alternatives to the trained practitioner is Greene and Wuts(Protective Groups In Organic Synthesis, Wiley and Sons, 1999).

Compounds of formula 1.5 are available as shown in Scheme 1. Adifferentially protected diamine 1.1 is singly deprotected and coupledwith a carboxylic acid 1.2 to provide the amide 1.3. For substrates withacid sensitive groups at R³ (i.e. tert-butyl esters or ethers), aselective removal of the N-Boc group is still readily achieved (Frank S.Gibson, et al, J. Org. Chem. 1994, 59, 3216). The other terminus of thediamine subunit of 1.3 is revealed by hydrogenation, and the nascentamine is readily conjugated with aldehydes 1.6 (R¹⁶=H) and ketones 1.6under reductive conditions (MeOH, NaCNBH₃ or THF, AcOH, NaHB(OAc)₃) toprovide the desired secondary amine 1.5. The chemistry shown in Scheme 1is quite general, as a wide array of aldehydes 1.6 (R¹⁶=H) and ketones1.6 are commercially available. Thus, the primary challenge in producingcompounds of formula 1.5 lies in two areas: the synthesis of thedifferentially protected diamines 1.1 and the synthesis of appropriatecarboxylic acids 1.2. The synthesis of a number of relevantdifferentially protected diamines 1.1 has been discussed by uspreviously (see: P. H. Carter, R. J. Cherney, WO-PCT 0250019, 2002,which is herein incorporated by reference). Two general syntheses ofappropriate carboxylic acids 1.2 are shown in Schemes 2 and 3. Manyother carboxylic acids 1.2, including those with n=0 and Z=bond, areeither commercially available or readily prepared. Specific embodimentsof this invention are described in the “Examples” section; this sectionalso details alternative synthetic pathways to compounds of formula 1.5.

A series of manolamide variants of formula 1.2 are synthesized as shownin Scheme 2. Several malonic acid mono-esters 2.1 are commerciallyavailable and can be coupled to commercially available amines to providethe malonamides 2.2. Removal of R through the appropriate methodology(hydrolysis with LiOH or KOH; or hydrogenolysis with Pd/C and H₂)affords the carboxylates 2.3.

A series of heterocyclic variants of 1.2 are synthesized as shown inScheme 3. Malonic acid mono-esters 2.1 can be coupled to mixed anilines3.1 to afford the amides 3.2. These amides (where X=OH, SH, NH₂,NHR^(5a)) can be cyclized to give 3.3 (K. Takeuchi et al. Bioorg. Med.Chem. Lett. 2000, 2347; G. Nawwar et al. Collect. Czech. Chem. Commun.1995, 2200; T. Hisano et al. Chem. Pharm. Bull. 1982, 2996). Compoundsof formula 3.3 can also be made directly through the condensation ofacids 2.1 and bifunctionalized anilines 3.1 under the appropriateconditions (G. Trapani et al. Eur. J. Med.

Chem. 1992, 39; P. Baudet et al. Helv. Chim. Acta. 1970, 1683; D.McKinnon et al. Can J. Chem. 1988, 2339; K.

Nivalkar et al. Synth. Commun. 1996, 3535). In either case, removal of Rfrom 3.3 through the appropriate methodology (hydrolysis with LiOH orKOH; or hydrogenolysis with Pd/C and H₂) affords the carboxylates 3.4.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

EXAMPLES

Abbreviations used in the Examples are defined as follows: “1×” foronce, “2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq”for equivalent or equivalents, “g” for gram or grams, “mg” for milligramor milligrams, “mL” for milliliter or milliliters, “¹H” for proton, “h”for hour or hours, “M” for molar, “min” for minute or minutes, “MHz” formegahertz, “MS” for mass spectroscopy, “NMR” for nuclear magneticresonance spectroscopy, “rt” for room temperature, “tic” for thin layerchromatography, “v/v” for volume to volume ratio. “α”, “β”, “R” and “S”are stereochemical designations familiar to those skilled in the art.

Example 1N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(2-trifluoromethyl-phenyl)-malonamide

(1a) A solution of mono-benzyl malonate (890 mg, 4.6 mmol) in 3:1CH₂Cl₂/DMF (24 mL) was treated sequentially withN,N-diisopropylethylamine (2.0 mL, 11.5 mmol),2-trifluoromethyl-phenylamine (0.6 mL, 4.6 mmol), and HATU (2.1 g, 5.5mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo,and partitioned between EtOAc and sat. NH₄Cl. The aqueous phase wasextracted with EtOAc (1×). The combined organic extracts were washedwith sat. NaHCO₃ and brine, dried (Na₂SO₄), filtered, and concentratedin vacuo. The residue was purified by flash chromatography to provideN-(2-trifluoromethyl-phenyl)-malonamic acid benzyl ester as an oil (894mg, 57% yield). This material was dissolved in EtOAc (35 mL). Theresultant solution was charged with 10% Pd/C (178 mg), stirred under H₂(1 atm) for 12 h at RT, filtered, and concentrated in vacuo to provideN-(2-trifluoromethyl-phenyl)-malonamic acid (621 mg, 95% yield). Aportion of this material (100 mg, 0.4 mmol) was combined with[(2S,3S)-2-amino-3-hydroxy-hex-4-ynyl]-carbamic acid benzyl ester (150mg, 0.4 mmol, prepared as described in WO PCT 0250019) and dissolved in6 mL of 3:1 CH₂Cl₂/DMF. The resultant solution was charged sequentiallywith N,N-diisopropylethylamine (0.35 mL, 1.5 mmol) and HATU (182 mg,0.48 mmol). The mixture was stirred for 12 h at RT, concentrated invacuo, and partitioned between EtOAc and sat. NH₄Cl. The aqueous phasewas extracted with EtOAc (1×). The combined organic extracts were washedwith sat. NaHCO₃ and brine, dried (Na₂SO₄), filtered, and concentratedin vacuo. The residue was purified by flash chromatography to provide{(2S,3S)-3-hydroxy-2-[2-(2-trifluoromethyl-phenylcarbamoyl)-acetylamino]-hex-4-ynyl}-carbamicacid benzyl ester (54 mg, 28% yield). MS found: (M+Na)⁺=514.5.

(1b) A solution of{(2S,3S)-3-hydroxy-2-[2-(2-trifluoromethyl-phenylcarbamoyl)-acetylamino]-hex-4-ynyl}-carbamicacid benzyl ester (54 mg, 0.11 mmol) in MeOH (2 mL) was charged with 5%Pd/C, Degussa style (10 mg), stirred under H₂ (1 atm) for 12 h at RT,filtered, and concentrated in vacuo. The residue was dissolved in MeOH(2 mL). The resultant solution was charged sequentially with2,4-dimethylbenzaldehyde and sodium cyanoborohydride, stirred for 12 hat RT, quenched with sat. NaHCO₃, and extracted twice with EtOAc. Theorganic extracts were combined, washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. Purification of the residue byreverse-phase HPLC provided the title compound as a white powder afterlyopholization. MS found: (M+H)⁺=480.6.

Example 2N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-trifluoromethyl-phenyl)-malonamide

(2a) The procedure 1a was repeated, substituting3-trifluoromethyl-phenylamine for 2-trifluoromethyl-phenylamine. Thepurified product was then carried through procedure 1b to afford thetitle compound as a white powder after reverse-phase HPLC andlyopholization. MS found: (M+H)⁺=480.3.

Example 3N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(4-trifluoromethyl-phenyl)-malonamide

(3a) The procedure 1a was repeated, substituting4-trifluoromethyl-phenylamine for 2-trifluoromethyl-phenylamine. Thepurified product was then carried through procedure 1b to afford thetitle compound as a white powder after reverse-phase HPLC andlyopholization. MS found: (M+H)⁺=480.5.

Example 4[2-(2-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentylcarbamoyl}-acetylamino)-4-trifluoromethyl-phenyl]-carbamicacid tert-butyl ester

(4a) A solution of 2-nitro-4-trifluoromethyl-phenylamine (5.0 g, 24.3mmol) in THF (150 mL) was cooled to −78° C. and treated with NaHMDS(53.5 mL of a 1.0 M THF solution, 53 mmol). The solution was stirred for1 h at −78° C. and then charged with a solution ofdi-(tert-butyl)dicarbonate (5.3 g, 24.3 mmol) in THF (50 mL); thereaction was allowed to warm to RT in the melting cold bath whilestirring for 12 h. The mixture was concentrated in vacuo and the residuewas dissolved in EtOAc. This solution was washed with 1N HCl (3×), H₂O(2×), and brine (1×) before being dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified via flash chromatographyto afford (2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butylester (5.3 g, 71% yield). The entirity of this material was dissolved inMeOH (120 mL). The resultant solution was charged with 5% Pd/C, Degussastyle (10 mg), stirred under H₂ (1 atm) for 12 h at RT, filtered, andconcentrated in vacuo to afford(2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (4.47g, 95% yield). ¹H-NMR (CD₃OD, 300 MHz): δ 1.52 (s, 9H), 6.91 (d, 1H),7.04 (s, 1H), 7.42 (d, 1H); ¹⁹F-NMR (CD₃OD, 300 MHz): δ −64.3 (s).

(4b) The procedure 1a was repeated, substituting(2-amino-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester for2-trifluoromethyl-phenylamine. The purified product was then carriedthrough procedure 1b to afford the title compound as a white powderafter reverse-phase HPLC and lyopholization. MS found: (M+H)⁺=595.5.

Example 5N-(2-Amino-5-trifluoromethyl-phenyl)-N′-{((1S,2S)-1-[(2,4-dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-malonamide

(5a) The compound[2-(2-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentylcarbamoyl}-acetylamino)-4-trifluoromethyl-phenyl]-carbamicacid tert-butyl ester (24 mg, 0.04 mmol, see procedure 4b above) wasdissolved in CH₂Cl₂ (1.5 mL) and treated with TFA (0.5 mL). The solutionwas stirred for 3 h and then concentrated in vacuo. The residue wasdissolved in benzene and concentrated in vacuo; this procedure wasrepeated. The residue was purified by reverse-phase HPLC to afford thetitle compound as a white powder after lyopholization. MS found:(M+H)⁺=495.2.

Example 6N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-trifluoromethoxy-phenyl)-malonamide

(6a) The procedure 1a was repeated, substitutingmeta-trifluoromethoxyaniline for 2-trifluoromethyl-phenylamine. Thepurified product was then carried through procedure 1b to afford thetitle compound as a white powder after reverse-phase HPLC andlyopholization. MS found: (M+H)⁺=496.4.

Example 7N-(3,5-Bis-trifluoromethyl-phenyl)-N′-{(1S,2S)-1-[(2,4-dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-malonamide

(7a) The procedure 1a was repeated, substituting3,5-bis(trifluoromethyl)aniline for 2-trifluoromethyl-phenylamine. Thepurified product was then carried through procedure 1b to afford thetitle compound as a white powder after reverse-phase HPLC andlyopholization. MS found: (M+H)⁺=548.3.

Example 8[3-(2-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentylcarbamoyl}-acetylamino)-5-trifluoromethyl-phenyl]-carbamicacid tert-butyl ester

(8a) A solution of 5-trifluoromethyl-benzene-1,3-diamine (1.0 g, 5.8mmol) in THF (25 mL) was cooled to −78° C. and treated with NaHMDS (12mL of a 1.0 M THF solution, 12 mmol). The solution was stirred for 1 hat −78° C. and then charged with a solution ofdi-(tert-butyl)dicarbonate (1.3 g, 5.8 mmol) in THF (10 mL); thereaction was allowed to warm to RT in the melting cold bath whilestirring for 12 h. The mixture was concentrated in vacuo and the residuewas dissolved in EtOAc. This solution was washed with 1N HCl (3×), H₂O(2×), and brine (1×) before being dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified via flash chromatographyto afford (3-amino-5-trifluoromethyl-phenyl)-carbamic acid tert-butylester (1.1 g, 68% yield). ¹H-NMR (CD₃OD, 300 MHz): δ 1.51 (s, 9H), 6.57(s, 1H), 6.96 (s, 1H), 6.99 (s, 1H); ¹⁹F-NMR (CD₃OD, 300 MHz): δ −64.95(s)

(8b) The procedure 1a was repeated, substituting(3-amino-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester for2-trifluoromethyl-phenylamine. The purified product was then carriedthrough procedure 1b to afford the title compound as a white powderafter reverse-phase HPLC and lyopholization. MS found: (M+H)⁺=595.5.

Example 9N-(3-Amino-5-trifluoromethyl-phenyl)-N′-{(1S,2S)-1-[(2,4-dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-malonamide

(9a) The compound[3-(2-{(1S,2S)-1-[(2,4-dimethyl-benzylamino)-methyl]-2-hydroxy-pentylcarbamoyl}-acetylamino)-5-trifluoromethyl-phenyl]-carbamicacid tert-butyl ester (45 mg, 0.08 mmol, see procedure 8b above) wasdissolved in CH₂Cl₂ (1.5 mL) and treated with TFA (0.5 mL). The solutionwas stirred for 3 h and then concentrated in vacuo. The residue wasdissolved in benzene and concentrated in vacuo; this procedure wasrepeated. The residue was purified by reverse-phase HPLC to afford thetitle compound as a white powder after lyopholization. MS found:(M+H)⁺=495.4.

Example 10N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-methoxy-5-trifluoromethyl-phenyl)-malonamide

(¹⁰a) The procedure 1a was repeated, substituting3-methoxy-5-trifluoromethyl-phenylamine for2-trifluoromethyl-phenylamine. The purified product was then carriedthrough procedure 1b to afford the title compound as a white powderafter reverse-phase HPLC and lyopholization. MS found: (M+H)⁺=510.4.

Example 11N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(2-methoxy-5-trifluoromethyl-phenyl)-malonamide

(11a) The procedure 1a was repeated, substituting2-methoxy-5-trifluoromethyl-phenylamine for2-trifluoromethyl-phenylamine. The purified product was then carriedthrough procedure 1b to afford the title compound as a white powderafter reverse-phase HPLC and lyopholization. MS found: (M+H)⁺=510.4.

Example 12N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-propylamino-5-trifluoromethyl-phenyl)-malonamide

(12a) A solution of{(2S,3S)-(2-tert-butoxycarbonylamino-3-hydroxy-hex-4-ynyl)-carbamic acidbenzyl ester (1.7 g, 4.8 mmol, prepared as described in WO PCT 0250019)in MeOH (72 mL) was charged with 5% Pd/C, Degussa style (350 mg),stirred under H₂ (1 atm) for 12 h at RT, filtered, and concentrated invacuo. The residue was dissolved in MeOH (47 mL). The resultant solutionwas charged sequentially with 2,4-dimethylbenzaldehyde (0.66 mL, 4.7mmol) and sodium cyanoborohydride (360 mg, 5.7 mmol), stirred for 12 hat RT, quenched with sat. NaHCO₃, and extracted twice with EtOAc. Theorganic extracts were combined, washed with brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The residue was dissolved in THF(66 mL). The resultant solution was charged sequentially withtriethylamine (1.2 mL, 9.0 mmol) and dibenzyldicarbonate (1.5 g, 5.4mmol), stirred for 36 h at RT, quenched with sat. NH₄Cl, and extractedtwice with EtOAc. The organic extracts were combined, washed with brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue waspurified by flash chromatography to afford(1S,2S)-(1-([benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentyl)-carbamicacid tert-butyl ester as a clear and colorless oil (2.0 g, 86% yield).MS found: (M+Na)⁺=507.4.

(12b) The compound(1S,2S)-(1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentyl)-carbamicacid tert-butyl ester (515 mg, 1.06 mmol) was dissolved in CH₂Cl₂ (12mL) and treated with TFA (4 mL). The solution was stirred for 3 h andthen concentrated in vacuo. The residue was dissolved in benzene andconcentrated in vacuo; this procedure was repeated. The resultant aminewas dissolved in 15 mL of 2:1 CH₂Cl₂/DMF. The resultant solution wascharged sequentially withN-(3-tert-butoxycarbonylamino-5-trifluoromethyl-phenyl)-malonamic acid(400 mg, 1.1 mmol, see examples 8 and 1), N,N-diisopropylethylamine(0.96 mL, 5.5 mmol) and HATU (504 mg, 1.3 mmol). The mixture was stirredfor 12 h at RT, concentrated in vacuo, and partitioned between EtOAc andsat. NH₄Cl. The aqueous phase was extracted with EtOAc (1×). Thecombined organic extracts were washed with sat. NaHCO₃ and brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The residue was purifiedby flash chromatography to provide(3-{2-[(1S,2S)-1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentylcarbamoyl]-acetylamino}-5-trifluoromethyl-phenyl)-carbamicacid tert-butyl ester (577 mg, 75% yield). MS found: (M+Na)⁺=751.4.

(12c) The compound(3-{2-[(1S,2S)-1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentylcarbamoyl]-acetylamino}-5-trifluoromethyl-phenyl)-carbamicacid tert-butyl ester (577 mg, 0.79 mmol) was dissolved in CH₂Cl₂ (12mL) and treated with TFA (4 mL). The solution was stirred for 3 h andthen concentrated in vacuo. The residue was dissolved in benzene andconcentrated in vacuo; this procedure was repeated to provide{(2S,3S)-2-[2-(3-amino-5-trifluoromethyl-phenylcarbamoyl)-acetylamino]-3-hydroxyhexyl}-(2,4-dimethyl-benzyl)-carbamicacid benzyl ester (100% yield). MS found: (M+H)⁺=629.4.

(12d) A solution of{(2S,3S)-2-[2-(3-amino-5-trifluoromethyl-phenylcarbamoyl)-acetylamino]-3-hydroxyhexyl}-(2,4-dimethyl-benzyl)-carbamicacid benzyl ester (97 mg, 0.15 mmol) in MeOH (3 mL) was charged withpropionaldehyde (0.01 mL, 0.15 mmol), stirred for 15 min at RT, and thencharged with sodium cyanoborohydride (12 mg, 0.19 mmol). The reactionwas stirred at RT for 12 h, concentrated in vacuo, and dissolved inEtOAc. The resultant solution was washed successively with water, sat.NaHCO₃, water, and brine. The organic phase was dried (Na₂SO₄),filtered, and concentrated in vacuo. The residue was dissolved in MeOH(3 mL). This solution was charged with 5% Pd/C, Degussa style (11 mg),stirred under H₂ (1 atm) for 12 h at RT, filtered, and concentrated invacuo. Purification of the residue by reverse-phase HPLC provided thetitle compound as a white powder after lyopholization. MS found:(M+H)⁺=537.4.

Example 13N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-dipropylamino-5-trifluoromethyl-phenyl)-malonamide

(13a) In the purification detailed in procedure 12d, the title compoundwas isolated as pure fraction. Lyopholization provided the titlecompound as a white powder. MS found: (M+H)⁺=579.4.

Example 14N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-methylamino-5-trifluoromethyl-phenyl)-malonamide

(14a) A solution of{(2S,3S)-2-[2-(3-amino-5-trifluoromethyl-phenylcarbamoyl)-acetylamino]-3-hydroxyhexyl}-(2,4-dimethyl-benzyl)-carbamicacid benzyl ester (83 mg, 0.13 mmol, see procedure 12c) in1,2-dichloroethane (2 mL) was charged with formaldehyde (0.008 mL of a37% aq. solution, 0.10 mmol), stirred for 20 min at RT, and then chargedwith sodium triacetoxyborohydride (69 mg, 0.33 mmol). The reaction wasstirred at RT for 40 min, quenched with water, and extracted with EtOAc(2×). The organic extracts were washed with water and brine, and thendried (Na₂SO₄), filtered, and concentrated in vacuo. The residue wasdissolved in MeOH (2 mL). This solution was charged with 5% Pd/C,Degussa style (7 mg), stirred under H₂ (1 atm) for 12 h at RT, filtered,and concentrated in vacuo. Purification of the residue by reverse-phaseHPLC provided the title compound as a white powder after lyopholization.MS found: (M+H)⁺=509.3.

Example 15N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-ethylamino-5-trifluoromethyl-phenyl)-malonamide

(15a) The procedure 12d was repeated, substituting acetaldehyde forpropionaldehyde, to afford the title compound as a white powder afterreverse-phase HPLC and lyopholization. MS found: (M+H)⁺=523.3.

Example 16N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-[3-(3-ethyl-ureido)-5-trifluoromethyl-phenyl]-malonamide

(16a) A solution of{(2S,3S)-2-[2-(3-amino-5-trifluoromethyl-phenylcarbamoyl)-acetylamino]-3-hydroxyhexyl}-(2,4-dimethyl-benzyl)-carbamicacid benzyl ester (110 mg, 0.18 mmol, see procedure 12c) in THF (4 mL)was charged with trichloroacetylchloride (0.063 mL, 0.53 mmol). Thereaction was stirred for 12 h at RT and concentrated in vacuo. Theresidue was dissolved in THF (4 mL). The resultant solution was chargedwith ethylamine (0.175 mL of a 2.0 M solution in THF, 0.35 mmol). Thereaction was stirred for 4 h at RT and concentrated in vacuo. Theresidue was dissolved in EtOAc and washed successively with water andbrine. The organic phase was dried (Na₂SO₄), filtered, and concentratedin vacuo. The residue was purified via flash chromatography to afford(2,4-dimethyl-benzyl)-[(2S,3S)-2-{2-[3-(3-ethyl-ureido)-5-trifluoromethyl-phenylcarbamoyl]-acetylamino}-3-hydroxy-hexyl]-carbamicacid benzyl ester as an oil (55 mg, 45% yield). MS found:

(M+Na)⁺=722.4.

(16b) The compound(2,4-dimethyl-benzyl)-[(2S,3S)-2-{2-[3-(3-ethyl-ureido)-5-trifluoromethyl-phenylcarbamoyl]-acetylamino}-3-hydroxy-hexyl]-carbamicacid benzyl ester was dissolved in MeOH (2 mL). This solution wascharged with 5% Pd/C, Degussa style (11 mg), stirred under H₂ (1 atm)for 12 h at RT, filtered, and concentrated in vacuo. Purification of theresidue by reverse-phase HPLC provided the title compound as a whitepowder after lyopholization. MS found: (M+H)⁺=566.3.

Example 17N-{(1S,2S)-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(4-methyl-3-trifluoromethyl-phenyl)-malonamide

(17a) The compound(1S,2S)-(1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentyl)-carbamicacid tert-butyl ester (580 mg, 1.2 mmol, see procedure 12a) wasdissolved in CH₂Cl₂ (9 mL) and treated with TFA (3 mL). The solution wasstirred for 3 h and then concentrated in vacuo. The residue wasdissolved in benzene and concentrated in vacuo; this procedure wasrepeated to provide[(2S,3S)-2-amino-3-hydroxy-hexyl]-(2,4-dimethyl-benzyl)-carbamic acidbenzyl ester. The amine was dissolved in 12 mL of 2:1 CH₂Cl₂/DMF. Theresultant solution was charged sequentially with mono-benzyl malonate(232 mg, 1.2 mmol), N,N-diisopropylethylamine (1.05 mL, 6.0 mmol) andHATU (547 mg, 1.4 mmol). The mixture was stirred for 12 h at RT,concentrated in vacuo, and partitioned between EtOAc and sat. NH₄Cl. Theaqueous phase was extracted with EtOAc (1×). The combined organicextracts were washed with sat. NaHCO₃ and brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The residue was purified by flashchromatography to provideN-[(1S,2S)-(1-{([benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentyl)]-malonamicacid benzyl ester (517 mg, 77% yield). MS found: (M+Na)⁺=583.4.

(17b) The compoundN-[(1S,2S)-(1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentyl)]-malonamicacid benzyl ester (517 mg, 0.92 mmol) was dissolved in THF (57 mL). Thissolution was charged sequentially with MeOH (19 mL) and aq. LiOH (44 mgLiOH in 19 mL water) and stirred for 12 h at RT. The mixture wasconcentrated in vacuo, and the residue was lyopholized from 1:1acetonitrile/water to provide the lithium salt ofN-[(1S,2S)-1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentyl]-malonamicacid as a white powder (420 mg, 97% yield). A portion of this material(39 mg, 0.22 mmol) was dissolved in 4 mL of 1:1 CH₂Cl₂/DMF. Theresultant solution was charged sequentially with4-methyl-3-trifluoromethylaniline (105 mg, 0.22 mmol),N,N-diisopropylethylamine (0.19 mL, 1.1 mmol) and HATU (102 mg, 0.27mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo,and partitioned between EtOAc and sat. NH₄Cl. The aqueous phase wasextracted with EtOAc (1×). The combined organic extracts were washedwith sat. NaHCO₃ and brine, dried (Na₂SO₄), filtered, and concentratedin vacuo. The residue was dissolved in MeOH (3 mL). This solution wascharged with 5% Pd/C, Degussa style (11 mg), stirred under H₂ (1 atm)for 12 h at RT, filtered, and concentrated in vacuo. Purification of theresidue by reverse-phase HPLC provided the title compound as a whitepowder after lyopholization. MS found: (M+H)⁺=494.4.

Example 18N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(4-methoxy-3-trifluoromethyl-phenyl)-malonamide

(18a) The procedure 17b was repeated, substituting4-methoxy-3-trifluoromethylaniline for4-methyl-3-trifluoromethylaniline, to afford the title compound as awhite powder after reverse-phase HPLC and lyopholization. MS found:(M+H)⁺=510.3.

Example 19N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(2-methyl-5-trifluoromethyl-phenyl)-malonamide

(19a) The procedure 17b was repeated, substituting2-methyl-5-trifluoromethylaniline for 4-methyl-3-trifluoromethylaniline,to afford the title compound as a white powder after reverse-phase HPLCand lyopholization. MS found: (M+H)⁺=494.3.

Example 20N-(3-Bromo-5-trifluoromethyl-phenyl)-N′-{(1S,2S)-1-[(2,4-dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-malonamide

(20a) The compoundN-[(1S,2S)-1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentyl]-malonamicacid (53 mg, 0.22 mmol, see procedure 17b) was dissolved in 4 mL of 1:1CH₂Cl₂/DMF. The resultant solution was charged sequentially with3-bromo-5-trifluoromethylaniline (105 mg, 0.22 mmol),N,N-diisopropylethylamine (0.19 mL, 1.1 mmol) and HATU (102 mg, 0.27mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo,and partitioned between EtOAc and sat. NH₄Cl. The aqueous phase wasextracted with EtOAc (1×). The combined organic extracts were washedwith sat. NaHCO₃ and brine, dried (Na₂SO₄), filtered, and concentratedin vacuo. A portion (25 mg) of this product was dissolved in 30%HBr/Acetic acid (2 mL). The solution was stirred for 4 h at RT andconcentrated in vacuo. The residue was dissolved in benzene and theresultant solution was concentrated residue; this procedure wasrepeated. Purification of the residue by reverse-phase HPLC provided thetitle compound as a white powder after lyopholization. MS found:(M+H)⁺=560.2.

Example 21N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-dimethylcarbamoyl-5-trifluoromethyl-phenyl)-malonamide

(21a) The compound [(2S,3S)-2-amino-3-hydroxy-hex-4-ynyl]-carbamic acidbenzyl ester (1.45 g, 3.8 mmol, prepared as described in WO PCT 0250019)was dissolved in 38 mL of 1:1 CH₂Cl₂/DMF. The resultant solution wascharged sequentially with mono-benzyl malonate (745 mg, 3.8 mmol),N,N-diisopropylethylamine (6.7 mL, 38 mmol) and HATU (1.75 g, 4.6 mmol).The mixture was stirred for 12 h at RT, concentrated in vacuo, andpartitioned between EtOAc and sat. NH₄Cl. The aqueous phase wasextracted with EtOAc (1×). The combined organic extracts were washedwith sat. NaHCO₃ and brine, dried (Na₂SO₄), filtered, and concentratedin vacuo. The residue was purified by flash chromatography to provideN-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-malonamicacid benzyl ester (1.5 g, 91% yield). MS found: (M+H)⁺=439.4. Theentirity of this material was dissolved in THF (18 mL). This solutionwas charged sequentially with MeOH (6 mL) and aq. LiOH (84 mg LiOH in 6mL water) and stirred for 12 h at RT. The mixture was concentrated invacuo, and the residue was lyopholized from 1:1 acetonitrile/water toprovide the lithium salt ofN-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-malonamicacid. MS found: (M+H)⁺=355.3.

(21b) The compound 3-nitro-5-trifluoromethylbenzoic acid (500 mg, 2.1mmol) was dissolved in 20 mL of 1:1 CH₂Cl₂/DMF. The resultant solutionwas charged sequentially with dimethylamine hydrochloride (174 mg, 2.1mmol), N,N-diisopropylethylamine (3.7 mL, 21 mmol) and HATU (970 mg, 2.6mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo,and partitioned between EtOAc and sat. NH₄Cl. The aqueous phase wasextracted with EtOAc (1×). The combined organic extracts were washedwith sat. NaHCO₃ and brine, dried (Na₂SO₄), filtered, and concentratedin vacuo. A portion (107 mg) of this product was dissolved in MeOH (6mL). This solution was charged with 5% Pd/C, Degussa style (21 mg),stirred under H₂ (1 atm) for 12 h at RT, filtered, and concentrated invacuo. The residue was dissolved in 6 mL of 1:1 CH₂Cl₂/DMF. Theresultant solution was charged sequentially with the lithium salt ofN-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-malonamicacid (141 mg, 0.4 mmol, see procedure 21a), N, N-diisopropylethylamine(0.35 mL, 2.0 mmol) and HATU (182 mg, 0.5 mmol). The mixture was stirredfor 12 h at RT, concentrated in vacuo, and partitioned between EtOAc andsat. NH₄Cl. The aqueous phase was extracted with EtOAc (1×). Thecombined organic extracts were washed with sat. NaHCO₃ and brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The residue was purifiedby flash chromatography to afford{(2S,3S)-2-[2-(3-dimethylcarbamoyl-5-trifluoromethyl-phenylcarbamoyl)-acetylamino]-3-hydroxy-hex-4-ynyl}-carbamicacid benzyl ester as a colorless oil (186 mg, 81% yield). MS found:(M+Na)⁺=585.3.

(21c) A solution of{(2S,3S)-2-[2-(3-dimethylcarbamoyl-5-trifluoromethyl-phenylcarbamoyl)-acetylamino]-3-hydroxy-hex-4-ynyl}-carbamicacid benzyl ester (186 mg, 0.33 mmol) in MeOH (6 mL) was charged with 5%Pd/C, Degussa style (37 mg), stirred under H₂ (1 atm) for 12 h at RT,filtered, and concentrated in vacuo. The residue was dissolved in MeOH(6 mL). The resultant solution was charged sequentially with2,4-dimethylbenzaldehyde (46 mg, 0.33 mmol) and sodium cyanoborohydride(25 mg, 0.4 mmol), stirred for 12 h at RT, quenched with sat. NaHCO₃,and extracted twice with EtOAc. The organic extracts were combined,washed with brine, dried (Na₂SO₄), filtered, and concentrated in vacuo.Purification of the residue by reverse-phase HPLC provided the titlecompound as a white powder after lyopholization. MS found: (M+H)⁺=551.3.

Example 22N-{1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-ethylcarbamoyl-5-trifluoromethyl-phenyl)-malonamide

(22a) The procedure 21b was repeated, substituting ethylamine (2.0 M inTHF) for dimethylamine hydrochloride. The purified product was thencarried through procedure 21c to afford the title compound as a whitepowder after reverse-phase HPLC and lyopholization. MS found:(M+H)⁺=551.3.

Example 23N-(5-tert-Butyl-[1,3,4]thiadiazol-2-yl)-N′-{(1S,2S)-1-[(2,4-dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-malonamide

(23a) The compound 5-tert-butyl-[1,3,4]thiadiazol-2-ylamine (67 mg, 0.43mmol) was dissolved in 6 mL of 1:1 CH₂Cl₂/DMF. The resultant solutionwas charged sequentially with the lithium salt ofN-[(1S,2S)-1-(benzyloxycarbonylamino-methyl)-2-hydroxy-pent-3-ynyl]-malonamicacid (151 mg, 0.43 mmol, see procedure 21a), N, N-diisopropylethylamine(0.38 mL, 2.1 mmol) and HATU (194 mg, 0.51 mmol). The mixture wasstirred for 12 h at RT, concentrated in vacuo, and partitioned betweenEtOAc and sat. NH₄Cl. The aqueous phase was extracted with EtOAc (1×).The combined organic extracts were washed with sat. NaHCO₃ and brine,dried (Na₂SO₄), filtered, and concentrated in vacuo. The residue waspurified by flash chromatography to afford{(2S,3S)-2-[2-(5-tert-butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-acetylamino]-3-hydroxy-hex-4-ynyl}-carbamicacid benzyl ester as a colorless oil (90 mg, 43% yield). MS found:(M+Na)⁺=510.4.

(23b) A solution of {(25,3S)-2-[2-(5-tert-butyl-[1,3,4]thiadiazol-2-ylcarbamoyl)-acetylamino]-3-hydroxy-hex-4-ynyl}-carbamicacid benzyl ester (90 mg, 0.19 mmol) in MeOH (4 mL) was charged with 5%Pd/C, Degussa style (18 mg), stirred under H₂ (1 atm) for 12 h at RT,filtered, and concentrated in vacuo. The residue was dissolved in MeOH(3 mL). The resultant solution was charged sequentially with2,4-dimethylbenzaldehyde (0.02 mL, 0.14 mmol) and sodiumcyanoborohydride (11 mg, 0.18 mmol), stirred for 12 h at RT, quenchedwith sat. NaHCO₃, and extracted twice with EtOAc. The organic extractswere combined, washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. Purification of the residue by reverse-phase HPLCprovided the title compound as a white powder after lyopholization. MSfound: (M+H)⁺=476.5.

Example 24N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-2,2-dimethyl-N′-(3-trifluoromethyl-phenyl)-malonamide

(24a) The compound 2,2-dimethyl-malonic acid diethyl ester (0.5 mL, 2.6mmol) was dissolved in EtOH. The resultant solution was charged withpotassium hydroxide (84 mg, 2.1 mmol) and the resultant suspension wasstirred for 12 h at RT. The mixture was concentrated under reducedpressure to provide the potassium salt of 2,2-dimethyl-malonic acidmonoethyl ester (430 mg, 100% yield, based on KOH). A portion (369 mg)of this material was dissolved in 21 mL of 1:1 CH₂Cl₂/DMF. The resultantsolution was charged sequentially with meta-trifluoromethylaniline (0.27mL, 2.2 mmol), N,N-diisopropylethylamine (1.8 mL, 10.9 mmol) and HATU(990 mg, 2.6 mmol). The mixture was stirred for 12 h at RT, concentratedin vacuo, and partitioned between EtOAc and sat. NH₄Cl. The aqueousphase was extracted with EtOAc (1×). The combined organic extracts werewashed with sat. NaHCO₃ and brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. The residue was purified by flash chromatographyto afford 2,2-dimethyl-N-(3-trifluoromethyl-phenyl)-malonamic acid ethylester (425 mg, 65% yield). ¹H-NMR (CDCl₃, 300 MHz): δ 1.25 (t, 2H), 1.50(s, 6H), 4.19 (q, 3H) 7.29 (d, 1H), 7.37 (t, 1H), 7.63 (d, 1H), 7.82 (s,1H), 8.96 (broad s, 1H); ¹⁹F-NMR (CDCl₃, 300 MHz): δ −63.13 (s).

(24b) The compound 2,2-dimethyl-N-(3-trifluoromethyl-phenyl)-malonamicacid ethyl ester (425 mg, 1.4 mmol) was dissolved in THF (12 mL). Theresultant solution was charged sequentially with MeOH (4 mL) and aq.LiOH (32 mg LiOH in 4 mL water). The mixture was concentrated in vacuo,and the residue was lyopholized from 1:1 acetonitrile/water to providethe lithium salt of 2,2-dimethyl-N-(3-trifluoromethyl-phenyl)-malonamicacid. A portion (55 mg, 0.2 mmol) of this material was dissolved in 4 mLof 1:1 CH₂Cl₂/DMF. The resultant solution was charged sequentially with[(2S,3S)-2-amino-3-hydroxy-hexyl]-(2,4-dimethyl-benzyl)-carbamic acidbenzyl ester (71 mg, 0.2 mmol), N,N-diisopropylethylamine (0.16 mL, 0.98mmol) and HATU (89 mg, 0.24 mmol). The mixture was stirred for 12 h atRT, concentrated in vacuo, and partitioned between EtOAc and sat. NH₄Cl.The aqueous phase was extracted with EtOAc (1×). The combined organicextracts were washed with sat. NaHCO₃ and brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. This material was dissolved in MeOH(4 mL), and the resultant solution was charged with 5% Pd/C, Degussastyle (11 mg), stirred under H₂ (1 atm) for 12 h at RT, filtered, andconcentrated in vacuo. Purification of the residue by reverse-phase HPLCprovided the title compound as a white powder after lyopholization. MSfound: (M+H)⁺=508.5.

Example 25N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-(2R/S)-2-methyl-N′-(3-trifluoromethyl-phenyl)-malonamide

(25a) The compound [(2S,3S)-2-amino-3-hydroxy-hex-4-ynyl]-carbamic acidbenzyl ester (173 mg, 0.46 mmol, prepared as described in WO PCT0250019) was dissolved in 5 mL of 1:1 CH₂Cl₂/DMF. The resultant solutionwas charged sequentially with 2-methyl-malonic acid (54 mg, 0.46 mmol),meta-trifluoromethylaniline (0.06 mL, 0.46 mmol),N,N-diisopropylethylamine (0.8 mL, 4.6 mmol) and HATU (434 mg, 1.1mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo,and partitioned between EtOAc and sat. NH₄Cl. The aqueous phase wasextracted with EtOAc (1×). The combined organic extracts were washedwith sat. NaHCO₃ and brine, dried (Na₂SO₄), filtered, and concentratedin vacuo. The residue was purified by flash chromatography to provide{(2S,3S)-3-hydroxy-2-[2-(3-trifluoromethyl-phenylcarbamoyl)-propionylamino]-hex-4-ynyl}-carbamicacid benzyl ester (40 mg, 17% yield). MS found: (M+Na)⁺=528.4.

(25b) A solution of{(2S,3S)-3-hydroxy-2-[2-(3-trifluoromethyl-phenylcarbamoyl)-propionylamino]-hex-4-ynyl}-carbamicacid benzyl ester (40 mg, 0.08 mmol) in MeOH (2 mL) was charged with 5%Pd/C, Degussa style (8 mg), stirred under H₂ (1 atm) for 12 h at RT,filtered, and concentrated in vacuo. The residue was dissolved in MeOH(2 mL). The resultant solution was charged sequentially with2,4-dimethylbenzaldehyde (0.009 mL, 0.06 mmol) and sodiumcyanoborohydride (5 mg, 0.08 mmol), stirred for 12 h at RT, quenchedwith sat. NaHCO₃, and extracted twice with EtOAc. The organic extractswere combined, washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. Purification of the residue by reverse-phase HPLCprovided the title compound as a white powder after lyopholization. MSfound: (M+H)⁺=494.4.

Example 26N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-2,2-difluoro-N′-(3-trifluoromethyl-phenyl)-malonamide

(26a) To a solution of 2,2-difluoro-malonic acid diethyl ester (500 mg,2.5 mmol) in EtOH (10 mL) was added KOH (82 mg, 2.0 mmol). The resultantsuspension was stirred overnight and then concentrated in vacuo toprovide the potassium salt of 2,2-difluoro-malonic acid ethyl ester (208mg, 40% yield). This material (1.0 mmol) was dissolved in 9 mL of 1:1CH₂Cl₂/DMF. The resultant solution was charged sequentially withmeta-trifluoromethylaniline (0.13 mL, 1.0 mmol),N,N-diisopropylethylamine (0.9 mL, 5.0 mmol) and HATU (460 mg, 1.2mmol). The mixture was stirred for 12 h at RT, concentrated in vacuo,and partitioned between EtOAc and sat. NH₄Cl. The aqueous phase wasextracted with EtOAc (1×). The combined organic extracts were washedwith sat. NaHCO₃ and brine, dried (Na₂SO₄), filtered, and concentratedin vacuo to provide 2,2-difluoro-N-(3-trifluoromethyl-phenyl)-malonamicacid ethyl ester. MS found: (M−H)-=310.2.

(26b) A solution of(1S,2S)-(1-{[benzyloxycarbonyl-(2,4-dimethyl-benzyl)-amino]-methyl}-2-hydroxy-pentyl)-carbamicacid tert-butyl ester (600 mg, 1.2 mmol, see procedure 12a) in MeOH wascharged with 5% Pd/C, Degussa style (120 mg), stirred under H₂ (1 atm)for 12 h at RT, filtered, and concentrated in vacuo. The residue wasdissolved in methylene chloride (6 mL) and the resultant solution wascharged with trifluoroacetic acid (6 mL). The mixture was stirred for 3h at RT and concentrated in vacuo. The residue was dissolved in benzeneand the resultant solution was concentrated in vacuo; this procedure wasrepeated to provide(2S,3S)-2-amino-1-(2,4-dimethyl-benzylamino)-hexan-3-ol (321 mg). MSfound: (M+H)⁺=251.4.

(26c) The compound 2,2-difluoro-N-(3-trifluoromethyl-phenyl)-malonamicacid ethyl ester (314 mg, 1.0 mmol) was dissolved in THF (6 mL). Theresultant solution was charged sequentially with MeOH (2 mL) and aq.LiOH (24 mg LiOH in 2 mL water). The mixture was concentrated in vacuo,and the residue was lyopholized from 1:1 acetonitrile/water to providethe lithium salt of 2,2-difluoro-N-(3-trifluoromethyl-phenyl)-malonamicacid. A portion (106 mg, 0.4 mmol) of this material was dissolved in 4mL of 1:1 CH₂Cl₂/DMF. The resultant solution was charged sequentiallywith (2S,3S)-2-amino-1-(2,4-dimethyl-benzylamino)-hexan-3-ol (71 mg, 0.2mmol, see procedure 26b), N,N-diisopropylethylamine (0.37 mL, 2.1 mmol)and HATU (194 mg, 0.51 mmol). The mixture was stirred for 12 h at RT,concentrated in vacuo, and partitioned between EtOAc and sat. NH₄Cl. Theaqueous phase was extracted with EtOAc (1×). The combined organicextracts were washed with sat. NaHCO₃ and brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. Purification of the residue byreverse-phase HPLC provided the title compound as a white powder afterlyopholization. MS found: (M+H)⁺=516.3.

Example 27N-(3-Amino-5-trifluoromethyl-phenyl)-N′-{(1S,2S)-1-[(2,4-dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-2,2-difluoro-malonamide

(27a) Procedure 26a was followed, substituting(3-amino-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (seeprocedure 8a) for meta-trifluoromethylaniline, and the resultant productwas carried through procedure 26c. The product residue was dissolved inmethylene chloride (3 mL), and the resultant solution was charged withtrifluoroacetic acid (3 mL), stirred for 3 h at RT, and concentrated invacuo. The residue was dissolved in benzene and the resultant solutionwas concentrated in vacuo; this procedure was repeated. Purification ofthe residue by reverse-phase HPLC provided the title compound as a whitepowder after lyopholization. MS found: (M+H)⁺=531.3.

Example 28N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-2-(4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetamide

(28a) N-(2-Nitro-3-trifluoromethyl-phenyl)-acetamide (Helvetica 1947, p.107) (3.6 g) was dissolved in EtOH and heated to 105° C. prior to theaddition of 1N NaOH (60 ml) and 50% NaOH (10 ml). After 2.5 h, thereaction was cooled to rt and EtOAc was added. The organic layer waswashed with water and brine. Then it was dried and concentrated to givea crude 2-nitro-3-trifluoromethyl-phenylamine (2.79 g): ¹H NMR (CDCl₃, δppm, 300 mHz) 5.0 (s, 2H), 7.02 (d, 1H), 7.10 (d, 1H), 7.38 (t, 1H). Aportion (1.42 g) of this material was dissolved in MeOH (20 mL) prior tothe addition of 10% Pd/C (260 mg). The reaction was placed on a Parrapparatus under hydrogen at 60 psi for 3 h. The Pd/C was filtered offand solvent was concentrated to give3-trifluoromethyl-benzene-1,2-diamine (1.16 g): ¹H NMR (CDCl₃, δppm, 300mHz) 3.40 (s, 2H), 3.94 (s, 2H), 6.70 (t, 1H), 6.85 (d, 1H), 7.02 (d,1H). A portion (1.15 g) of this material was dissolved in diethylmalonate. The reaction was heated at 160° C. (oil bath temperature) for1.5 h. After cooling to rt, flash chromatography of the crude reactiongave (4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid ethyl ester(1.14 g). MS found: (M+H)⁺=273.0. A portion (200 mg) of this materialwas dissolved in THF (2 mL) prior to the addition of a solution ofLiOH.H₂O (37 mg) in water (0.1 ml). A couple drops of MeOH were addeduntil the solution became clear. After 2 h at rt, the reaction wasconcentrated and freeze-dried to provide(4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid lithium salt (175mg). MS found: (M+H)⁺=245.0

(28b) The compound [(2S,3S)-2-amino-3-hydroxy-hex-4-ynyl]-carbamic acidbenzyl ester (70 mg, 0.19 mmol, prepared as described in WO PCT 0250019)was dissolved in 5 mL of 2:1 CH₂Cl₂/DMF. The resultant solution wascharged sequentially with the lithium salt of(4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid (46 mg, 0.19 mmol,see procedure 28a), N,N-diisopropylethylamine (0.16 mL, 0.94 mmol) andHATU (85 mg, 0.22 mmol). The mixture was stirred for 12 h at RT,concentrated in vacuo, and partitioned between EtOAc and sat. NH₄Cl. Theaqueous phase was extracted with EtOAc (1×). The combined organicextracts were washed with sat. NaHCO₃ and brine, dried (Na₂SO₄),filtered, and concentrated in vacuo. The residue was purified by flashchromatography to provide{(2S,3S)-3-hydroxy-2-[2-(4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetylamino]-hex-4-ynyl}-carbamicacid benzyl ester (87 mg, 95% yield). MS found: (M+Na)⁺=511.3.

(28c) A solution of{(2S,3S)-3-hydroxy-2-[2-(4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetylamino]-hex-4-ynyl}-carbamicacid benzyl ester (87 mg, 0.18 mmol) in MeOH (3 mL) was charged with 5%Pd/C, Degussa style (17 mg), stirred under H₂ (1 atm) for 12 h at RT,filtered, and concentrated in vacuo. The residue was dissolved in MeOH(3 mL). The resultant solution was charged sequentially with2,4-dimethylbenzaldehyde (0.024 mL, 0.16 mmol) and sodiumcyanoborohydride (12 mg, 0.2 mmol), stirred for 12 h at RT, quenchedwith sat. NaHCO₃, and extracted twice with EtOAc. The organic extractswere combined, washed with brine, dried (Na₂SO₄), filtered, andconcentrated in vacuo. Purification of the residue by reverse-phase HPLCprovided the title compound as a white powder after lyopholization. MSfound: (M+H)⁺=477.4.

Example 29N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-2-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-acetamide

(29a) The compound (2-amino-4-trifluoromethyl-phenyl)-carbamic acidtert-butyl ester (1.8 g, 6.6 mmol, see procedure 4a) was dissolved in 32mL of 2:1 CH₂Cl₂/DMF. The resultant solution was charged sequentiallywith mono-benzyl malonate (1.28 g, 6.6 mmol), N,N-diisopropylethylamine(5.8 mL, 33 mmol) and HATU (3.0 g, 7.9 mmol). The mixture was stirredfor 12 h at RT, concentrated in vacuo, and partitioned between EtOAc andsat. NH₄Cl. The aqueous phase was extracted with EtOAc (1×). Thecombined organic extracts were washed with sat. NaHCO₃ and brine, dried(Na₂SO₄), filtered, and concentrated in vacuo. The residue was purifiedby flash chromatography to provideN-(2-tert-butoxycarbonylamino-5-trifluoromethyl-phenyl)-malonamic acidbenzyl ester (2.3 g, 77% yield). A portion (860 mg) of this material wasdissolved in 10 mL of THF. The resultant solution was charged with 30 mLof acetic acid, heated at 65° C. for 3 h, and concentrated in vacuo. Theresidue was purified by flash chromatography to provide(5-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid benzyl ester (343mg, 54% yield). MS found: (M+H)⁺=335.2.

(29b) The compound (5-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acidbenzyl ester (105 mg, 0.32 mmol) was dissolved in THF (3.6 mL). Theresultant solution was charged sequentially with MeOH (1.2 mL) and aq.LiOH (15 mg LiOH in 1.2 mL water), stirred for 12 h at RT, andconcentrated in vacuo (the water bath was left unheated) to provide thelithium salt of (5-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid.This material was incorporated into procedure 28b in the place of thelithium salt of (4-trifluoromethyl-1H-benzoimidazol-2-yl)-acetic acid.The resultant product was carried through procedure 28c to provide thetitle compound as a white powder after reverse-phase HPLC purificationand lyopholization. MS found: (M+H)⁺=477.5.

Table of Examples

The following table illustrates examples of the present invention. Thedata in the “MS” columns represent the values observed for the (M+H)⁺ions in electrospray mass spectroscopy experiments. The substituentslisted in each table are to be paired with the structure embedded in thetable heading. The synthesis of all of these compounds has beendescribed in detail in the previous section (Examples).

TABLE 1

examples 1–29 R¹⁴, No. R¹ R³ R^(14a) Z R² MS 1

H

480.6 2

H

480.3 3

H

480.5 4

H

595.5 5

H

495.2 6

H

496.4 7

H

548.3 8

H

595.5 9

H

495.4 10

H

510.4 11

H

510.4 12

H

537.4 13

H

579.4 14

H

509.3 15

H

523.3 16

H

566.3 17

H

494.4 18

H

510.3 19

H

494.3 20

H

560.2 21

H

551.3 22

H

551.3 23

H

476.5 24

Me₂

508.5 25

Me

494.4 26

F₂

516.3 27

F₂

531.3 28

H —

477.4 29

H —

477.5

Utility

Compounds of formula I are shown to be modulators of chemokine receptoractivity using assays know by those skilled in the art. In this section,we describe these assays and give their literature reference. Bydisplaying activity in these assays of MCP-1 antagonism, compounds offormula I are expected to be useful in the treatment of human diseasesassociated with chemokines and their cognate receptors. The definitionof activity in these assays is a compound demonstrating an IC₅₀ of 20 μMor lower in concentration when measured in a particular assay.

Antagonism of MCP-1 Binding to Human PBMC

(Yoshimura et al., J. Immunol. 1990, 145, 292)

Compounds of the present invention have activity in the antagonism ofMCP-1 binding to human PBMC (human peripheral blood mononuclear cells)described here.

Millipore filter plates (#MABVN1250) are treated with 100 μl of bindingbuffer (0.5% bovine serum albumin, 20 mM HEPES buffer and 5 mM magnesiumchloride in RPMI 1640 media) for thirty minutes at room temperature. Tomeasure binding, 50 μl of binding buffer, with or without a knownconcentration compound, is combined with 50 μl of ¹²⁵-I labeled humanMCP-1 (to give a final concentration of 150 μM radioligand) and 50 μl ofbinding buffer containing 5×10⁵ cells. Cells used for such bindingassays can include human peripheral blood mononuclear cells isolated byFicoll-Hypaque gradient centrifugation, human monocytes (Weiner et al.,J. Immunol. Methods. 1980, 36, 89), or the THP-1 cell line whichexpresses the endogenous receptor. The mixture of compound, cells andradioligand are incubated at room temperature for thirty minutes. Platesare placed onto a vacuum manifold, vacuum applied, and the plates washedthree times with binding buffer containing 0.5M NaCl. The plastic skirtis removed from the plate, the plate allowed to air dry, the wellspunched out and counted. The percent inhibition of binding is calculatedusing the total counts obtained in the absence of any competing compoundand the background binding determined by addition of 100 nM MCP-1 inplace of the test compound.

Antagonism of MCP-1-Induced Calcium Influx

(Sullivan, et al. Methods Mol. Biol., 114, 125–133 (1999)

Compounds of the present invention have activity in the antagonism ofMCP-1-induced calcium influx assay described here.

Calcium mobilization is measured using the fluorescent Ca²⁺ indicatordye, Fluo-3. Cells are incubated at 8×10⁵ cells/ml in phosphate-bufferedsaline containing 0.1% bovine serum albumin, 20 mM HEPES buffer, 5 mMglucose, 1% fetal bovine serum, 4 μM Fluo-3 AM and 2.5 mM probenecid for60 minutes at 37° C. Cells used for such calcium assays can includehuman monocytes isolated as described by Weiner et al., J. Immunol.Methods, 36, 89–97 (1980) or cell lines which expresses the endogenousCCR2 receptor such as THP-1 and MonoMac-6. The cells are then washedthree times in phosphate-buffered saline containing 0.1% bovine serumalbumin, 20 mM HEPES, 5 mM glucose and 2.5 mM probenecid. The cells areresuspended in phosphate-buffered saline containing 0.5% bovine serumalbumin, 20 mM HEPES and 2.5 mM probenecid at a final concentration of2–4×10⁶ cells/ml. Cells are plated into 96-well, black-wall microplates(100 μl/well) and the plates centrifuged at 200×g for 5 minutes. Variousconcentrations of compound are added to the wells (50 μl/well) and after5 minutes, 50 μl/well of MCP-1 is added to give a final concentration of10 nM. Calcium mobilization is detected by using a fluorescent-imagingplate reader. The cell monolayer is excited with an argon laser (488 nM)and cell-associated fluorescence measured for 3 minutes, (every secondfor the first 90 seconds and every 10 seconds for the next 90 seconds).Data are generated as arbitrary fluorescence units and the change influorescence for each well determined as the maximum-minimumdifferential. Compound-dependent inhibition is calculated relative tothe response of MCP-1 alone.

Antagonism of MCP-1-induced Human PBMC Chemotaxis

(Bacon et al., Brit. J. Pharmacol. 1988, 95, 966)

Compounds of the present invention have activity in the antagonism ofMCP-1-induced human PBMC chemotaxis assay described here.

Neuroprobe MBA96-96-well chemotaxis chamber, Polyfiltronics MPC 96 wellplate, and Neuroprobe polyvinylpyrrolidone-free polycarbonate PFD58-micron filters are warmed in a 37° C. incubator. Human PeripheralBlood Mononuclear Cells (PBMCs) (Boyum et al., Scand. J. Clin. LabInvest. Suppl. 1968, 97, 31), freshly isolated via the standard ficolldensity separation method, are suspended in DMEM at 1×10⁷ c/ml andwarmed at 37° C. A 60 nM solution of human MCP-1 is also warmed at 37°C. Dilutions of test compounds are made up at 2× the concentrationneeded in DMEM. The PBMC suspension and the 60 nm MCP-1 solution aremixed 1:1 in polypropylene tubes with prewarmed DMEM with or without adilution of the test compounds. These mixtures are warmed in a 37° C.tube warmer. To start the assay, add the MCP-1/compound mixture into thewells of the Polyfiltronics MPC 96 well plate that has been placed intothe bottom part of the Neuroprobe chemotaxis chamber. The approximatevolume is 400 μl to each well and there should be a positive meniscusafter dispensing. The 8 micron filter is placed gently on top of the 96well plate, a rubber gasket is attached to the bottom of the upperchamber, and the chamber is assembled. A 200 μl volume of the cellsuspension/compound mixture is added to the appropriate wells of theupper chamber. The upper chamber is covered with a plate sealer, and theassembled unit is placed in a 37° C. incubator for 45 minutes. Afterincubation, the plate sealer is removed and all the remaining cellsuspension is aspirated off. The chamber is disassembled and the filtergently removed. While holding the filter at a 90 degree angle,unmigrated cells are washed away using a gentle stream of phosphatebuffered saline and the top of the filter wiped with the tip of a rubbersqueegee. Repeat this wash twice more. The filter is air dried and thenimmersed completely in Wright Geimsa stain for 45 seconds. The filter isthen washed by soaking in distilled water for 7 minutes, and then a 15second additional wash in fresh distilled water. The filter is again airdried. Migrated cells on the filter are quantified by visual microscopy.

Mammalian chemokine receptors provide a target for interfering with orpromoting immune cell function in a mammal, such as a human. Compoundsthat inhibit or promote chemokine receptor function are particularlyuseful for modulating immune cell function for therapeutic purposes.Accordingly, the present invention is directed to compounds which areuseful in the prevention and/or treatment of a wide variety ofinflammatory, infectious, and immunoregulatory disorders and diseases,including asthma and allergic diseases, infection by pathogenic microbes(which, by definition, includes viruses), as well as autoimmunepathologies such as the rheumatoid arthritis and atherosclerosis.

For example, an instant compound which inhibits one or more functions ofa mammalian chemokine receptor (e.g., a human chemokine receptor) may beadministered to inhibit (i.e., reduce or prevent) inflammation orinfectious disease. As a result, one or more inflammatory process, suchas leukocyte emigration, adhesion, chemotaxis, exocytosis (e.g., ofenzymes, histamine) or inflammatory mediator release, is inhibited.

Similarly, an instant compound which promotes one or more functions ofthe mammalian chemokine receptor (e.g., a human chemokine) asadministered to stimulate (induce or enhance) an immune or inflammatoryresponse, such as leukocyte emigration, adhesion, chemotaxis, exocytosis(e.g., of enzymes, histamine) or inflammatory mediator release,resulting in the beneficial stimulation of inflammatory processes. Forexample, eosinophils can be recruited to combat parasitic infections. Inaddition, treatment of the aforementioned inflammatory, allergic andautoimmune diseases can also be contemplated for an instant compoundwhich promotes one or more functions of the mammalian chemokine receptorif one contemplates the delivery of sufficient compound to cause theloss of receptor expression on cells through the induction of chemokinereceptor internalization or the delivery of compound in a manner thatresults in the misdirection of the migration of cells.

In addition to primates, such as humans, a variety of other mammals canbe treated according to the method of the present invention. Forinstance, mammals, including but not limited to, cows, sheep, goats,horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine,canine, feline, rodent or murine species can be treated. However, themethod can also be practiced in other species, such as avian species.The subject treated in the methods above is a mammal, male or female, inwhom modulation of chemokine receptor activity is desired. “Modulation”as used herein is intended to encompass antagonism, agonism, partialantagonism and/or partial agonism.

Diseases or conditions of human or other species which can be treatedwith inhibitors of chemokine receptor function, include, but are notlimited to: inflammatory or allergic diseases and conditions, includingrespiratory allergic diseases such as asthma, allergic rhinitis,hypersensitivity lung diseases, hypersensitivity pneumonitis,eosinophilic cellulitis (e.g., Well's syndrome), eosinophilic pneumonias(e.g., Loeffler's syndrome, chronic eosinophilic pneumonia),eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-typehypersensitivity, interstitial lung diseases (ILD) (e.g., idiopathicpulmonary fibrosis, or ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing spondylitis, systemicsclerosis, Sjogren's syndrome, polymyositis or dermatomyositis);systemic anaphylaxis or hypersensitivity responses, drug allergies(e.g., to penicillin, cephalosporins), eosinophilia-myalgia syndrome dueto the ingestion of contaminated tryptophan, insect sting allergies;autoimmune diseases, such as rheumatoid arthritis, psoriatic arthritis,multiple sclerosis, systemic lupus erythematosus, myasthenia gravis,juvenile onset diabetes; glomerulonephritis, autoimmune thyroiditis,Behcet's disease; graft rejection (e.g., in transplantation), includingallograft rejection or graft-versus-host disease; inflammatory boweldiseases, such as Crohn's disease and ulcerative colitis;spondyloarthropathies; scleroderma; psoriasis (including T-cell mediatedpsoriasis) and inflammatory dermatoses such as an dermatitis, eczema,atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis(e.g., necrotizing, cutaneous, and hypersensitivity vasculitis);eosinophilic myositis, eosinophilic fasciitis; cancers with leukocyteinfiltration of the skin or organs. Other diseases or conditions inwhich undesirable inflammatory responses are to be inhibited can betreated, including, but not limited to, reperfusion injury,atherosclerosis, certain hematologic malignancies, cytokine-inducedtoxicity (e.g., septic shock, endotoxic shock), polymyositis,dermatomyositis. Infectious diseases or conditions of human or otherspecies which can be treated with inhibitors of chemokine receptorfunction, include, but are not limited to, HIV.

Diseases or conditions of humans or other species which can be treatedwith promoters of chemokine receptor function, include, but are notlimited to: immunosuppression, such as that in individuals withimmunodeficiency syndromes such as AIDS or other viral infections,individuals undergoing radiation therapy, chemotherapy, therapy forautoimmune disease or drug therapy (e.g., corticosteroid therapy), whichcauses immunosuppression; immunosuppression due to congenital deficiencyin receptor function or other causes; and infections diseases, such asparasitic diseases, including, but not limited to helminth infections,such as nematodes (round worms); (Trichuriasis, Enterobiasis,Ascariasis, Hookworm, Strongyloidiasis, Trichinosis, filariasis);trematodes (flukes) (Schistosomiasis, Clonorchiasis), cestodes (tapeworms) (Echinococcosis, Taeniasis saginata, Cysticercosis); visceralworms, visceral larva migraines (e.g., Toxocara), eosinophilicgastroenteritis (e.g., Anisaki sp., Phocanema sp.), cutaneous larvamigraines (Ancylostona braziliense, Ancylostoma caninum). The compoundsof the present invention are accordingly useful in the prevention andtreatment of a wide variety of inflammatory, infectious andimmunoregulatory disorders and diseases. In addition, treatment of theaforementioned inflammatory, allergic and autoimmune diseases can alsobe contemplated for promoters of chemokine receptor function if onecontemplates the delivery of sufficient compound to cause the loss ofreceptor expression on cells through the induction of chemokine receptorinternalization or delivery of compound in a manner that results in themisdirection of the migration of cells.

In another aspect, the instant invention may be used to evaluate theputative specific agonists or antagonists of a G protein coupledreceptor. The present invention is directed to the use of thesecompounds in the preparation and execution of screening assays forcompounds that modulate the activity of chemokine receptors.Furthermore, the compounds of this invention are useful in establishingor determining the binding site of other compounds to chemokinereceptors, e.g., by competitive inhibition or as a reference in an assayto compare its known activity to a compound with an unknown activity.When developing new assays or protocols, compounds according to thepresent invention could be used to test their effectiveness.Specifically, such compounds may be provided in a commercial kit, forexample, for use in pharmaceutical research involving the aforementioneddiseases. The compounds of the instant invention are also useful for theevaluation of putative specific modulators of the chemokine receptors.In addition, one could utilize compounds of this invention to examinethe specificity of G protein coupled receptors that are not thought tobe chemokine receptors, either by serving as examples of compounds whichdo not bind or as structural variants of compounds active on thesereceptors which may help define specific sites of interaction.

The compounds of the present invention are used to treat or preventdisorders selected from rheumatoid arthritis, osteoarthritis, septicshock, atherosclerosis, aneurism, fever, cardiovascular effects,haemodynamic shock, sepsis syndrom, post ischemic reperfusion injury,malaria, Crohn's disease, inflammatory bowel diseases, mycobacterialinfection, meningitis, psoriasis, congestive heart failure, fibroticdiseases, cachexia, graft rejection, autoimmune diseases, skininflammatory diseases, multiple sclerosis, radiation damage, hyperoxicalveolar injury, HIV, HIV dementia, non-insulin dependent diabetesmelitus, asthma, allergic rhinitis, atopic dermatitis, idiopathicpulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections,allergic colitis, eczema, conjunctivitis, transplantation, familialeosinophilia, eosinophilic cellulitis, eosinophilic pneumonias,eosinophilic fasciitis, eosinophilic gastroenteritis, drug inducedeosinophilia, cystic fibrosis, Churg-Strauss syndrome, lymphoma,Hodgkin's disease, colonic carcinoma, Felty's syndrome, sarcoidosis,uveitis, Alzheimer, Glomerulonephritis, and systemic lupuserythematosus.

In another aspect, the compounds are used to treat or preventinflammatory disorders selected from from rheumatoid arthritis,osteoarthritis, atherosclerosis, aneurism, fever, cardiovasculareffects, Crohn's disease, inflammatory bowel diseases, psoriasis,congestive heart failure, multiple sclerosis, autoimmune diseases, skininflammatory diseases.

In another aspect, the compounds are used to treat or preventinflammatory disorders selected from rheumatoid arthritis,osteoarthritis, atherosclerosis, Crohn's disease, inflammatory boweldiseases, and multiple sclerosis.

Combined therapy to prevent and treat inflammatory, infectious andimmunoregulatory disorders and diseases, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis, and those pathologies noted above is illustrated bythe combination of the compounds of this invention and other compoundswhich are known for such utilities. For example, in the treatment orprevention of inflammation, the present compounds may be used inconjunction with an anti-inflammatory or analgesic agent such as anopiate agonist, a lipoxygenase inhibitor, a cyclooxygenase-2 inhibitor,an interleukin inhibitor, such as an interleukin-1 inhibitor, a tumornecrosis factor inhibitor, an NMDA antagonist, an inhibitor or nitricoxide or an inhibitor of the synthesis of nitric oxide, a non-steroidalanti-inflammatory agent, a phosphodiesterase inhibitor, or acytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, fentaynl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, interferon alpha and thelike. Similarly, the instant compounds may be administered with a painreliever; a potentiator such as caffeine, an H2-antagonist, simethicone,aluminum or magnesium hydroxide; a decongestant such as phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, or levodesoxy-ephedrine;and antitussive such as codeine, hydrocodone, caramiphen,carbetapentane, or dextramethorphan; a diuretic; and a sedating ornon-sedating antihistamine. Likewise, compounds of the present inventionmay be used in combination with other drugs that are used in thetreatment/prevention/suppression or amelioration of the diseases orconditions for which compound of the present invention are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefore, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention may be used. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

Examples of other active ingredients that may be combined with acompound of the present invention, either administered separately or inthe same pharmaceutical compositions, include, but are not limited to:(a) integrin antagonists such as those for selectins, ICAMs and VLA-4;(b) steroids such as beclomethasone, methylprednisolone, betamethasone,prednisone, dexamethasone, and hydrocortisone; (c) immunosuppressantssuch as cyclosporin, tacrolimus, rapamycin and other FK-506 typeimmunosuppressants; (d) antihistamines (H1-histamine antagonists) suchas bromopheniramine, chlorpheniramine, dexchlorpheniramine,triprolidine, clemastine, diphenhydramine, diphenylpyraline,tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine,azatadine, cyproheptadine, antazoline, pheniramine pyrilamine,astemizole, terfenadine, loratadine, cetirizine, fexofenadine,descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as b2-agonists (terbutaline, metaproterenol,fenoterol, isoetharine, albuteral, bitolterol, and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (zafirlukast, montelukast, pranlukast,iralukast, pobilukast, SKB-102,203), leukotriene biosynthesis inhibitors(zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs)such as propionic acid derivatives (alminoprofen, benxaprofen, bucloxicacid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen),acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, andzomepirac), fenamic acid derivatives (flufenamic acid, meclofenamicacid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams(isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone);(g) cyclooxygenase-2 (COX-2) inhibitors; (h) inhibitors ofphosphodiesterase type IV (PDE-IV); (I) other antagonists of thechemokine receptors; (j) cholesterol lowering agents such as HMG-COAreductase inhibitors (lovastatin, simvastatin and pravastatin,fluvastatin, atorvsatatin, and other statins), sequestrants(cholestyramine and colestipol), nicotonic acid, fenofibric acidderivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), andprobucol; (k) anti-diabetic agents such as insulin, sulfonylureas,biguanides (metformin), a-glucosidase inhibitors (acarbose) andglitazones (troglitazone ad pioglitazone); (1) preparations ofinterferons (interferon alpha-2a, interferon-2B, interferon alpha-N3,interferon beta-1a, interferon beta-1b, interferon gamma-1b); (m)antiviral compounds such as efavirenz, nevirapine, indinavir,ganciclovir, lamivudine, famciclovir, and zalcitabine; (o) othercompound such as 5-aminosalicylic acid an prodrugs thereof,antimetabolites such as azathioprine and 6-mercaptopurine, and cytotoxiccancer chemotherapeutic agents. The weight ratio of the compound of thepresent invention to the second active ingredient may be varied and willdepend upon the effective doses of each ingredient.

Generally, an effective dose of each will be used. Thus, for example,when a compound of the present invention is combined with an NSAID theweight ratio of the compound of the present invention to the NSAID willgenerally range from about 1000:1 to about 1:1000, or alternatively fromabout 200:1 to about 1:200. Combinations of a compound of the presentinvention and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of Formula I that, when administered alone or incombination with an additional therapeutic agent to a mammal, iseffective to prevent or ameliorate the thromboembolic disease conditionor the progression of the disease.

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, or between about 0.01 to 100mg/kg of body weight per day, or alternativley, between about 1.0 to 20mg/kg/day. Intravenously, the doses will range from about 1 to about 10mg/kg/minute during a constant rate infusion. Compounds of thisinvention may be administered in a single daily dose, or the total dailydosage may be administered in divided doses of two, three, or four timesdaily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels. Dosage forms(pharmaceutical compositions) suitable for administration may containfrom about 1 milligram to about 100 milligrams of active ingredient perdosage unit. In these pharmaceutical compositions the active ingredientwill ordinarily be present in an amount of about 0.5–95% by weight basedon the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract. Liquid dosage forms fororal administration can contain coloring and flavoring to increasepatient acceptance. In general, water, a suitable oil, saline, aqueousdextrose (glucose), and related sugar solutions and glycols such aspropylene glycol or polyethylene glycols are suitable carriers forparenteral solutions. Solutions for parenteral administration maycontain a water soluble salt of the active ingredient, suitablestabilizing agents, and if necessary, buffer substances. Antioxidizingagents such as sodium bisulfite, sodium sulfite, or ascorbic acid,either alone or combined, are suitable stabilizing agents. Also used arecitric acid and its salts and sodium EDTA. In addition, parenteralsolutions can contain preservatives, such as benzalkonium chloride,methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field. Representative useful pharmaceutical dosage-formsfor administration of the compounds of this invention can be illustratedas follows:

Capsules

A large number of unit capsules can be prepared by filling standardtwo-piece hard gelatin capsules each with 100 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil may be prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 100 milligrams of the active ingredient. The capsules shouldbe washed and dried.

Tablets

Tablets may be prepared by conventional procedures so that the dosageunit is 100 milligrams of active ingredient, 0.2 milligrams of colloidalsilicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams ofmicrocrystalline cellulose, 11 milligrams of starch and 98.8 milligramsof lactose. Appropriate coatings may be applied to increase palatabilityor delay absorption.

Injectable

A parenteral composition suitable for administration by injection may beprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution should be made isotonicwith sodium chloride and sterilized.

Suspension

An aqueous suspension can be prepared for oral administration so thateach 5 mL contain 100 mg of finely divided active ingredient, 200 mg ofsodium carboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g ofsorbitol solution, U.S.P., and 0.025 mL of vanillin. Where the compoundsof this invention are combined with other anticoagulant agents, forexample, a daily dosage may be about 0.1 to 100 milligrams of thecompound of Formula I and about 1 to 7.5 milligrams of the secondanticoagulant, per kilogram of patient body weight. For a tablet dosageform, the compounds of this invention generally may be present in anamount of about 5 to 10 milligrams per dosage unit, and the secondanti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination. Particularly when provided as asingle dosage unit, the potential exists for a chemical interactionbetween the combined active ingredients. For this reason, when thecompound of Formula I and a second therapeutic agent are combined in asingle dosage unit they are formulated such that although the activeingredients are combined in a single dosage unit, the physical contactbetween the active ingredients is minimized (that is, reduced). Forexample, one active ingredient may be enteric coated. By enteric coatingone of the active ingredients, it is possible not only to minimize thecontact between the combined active ingredients, but also, it ispossible to control the release of one of these components in thegastrointestinal tract such that one of these components is not releasedin the stomach but rather is released in the intestines. One of theactive ingredients may also be coated with a material which effects asustained-release throughout the gastrointestinal tract and also servesto minimize physical contact between the combined active ingredients.Furthermore, the sustained-released component can be additionallyenteric coated such that the release of this component occurs only inthe intestine. Still another approach would involve the formulation of acombination product in which the one component is coated with asustained and/or enteric release polymer, and the other component isalso coated with a polymer such as a lowviscosity grade of hydroxypropylmethylcellulose (HPMC) or other appropriate materials as known in theart, in order to further separate the active components. The polymercoating serves to form an additional barrier to interaction with theother component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that within the scope of the appended claims, theinvention may be practiced otherwise that as specifically describedherein.

1. A compound of Formula (I)

or a stereoisomer or a pharmaceutically acceptable salt thereof,wherein: Z is selected from a bond, —C(O)—, and —C(O)NR¹⁸; Q is selectedfrom O or S; X is —CHR¹⁶NR¹⁷—; R^(a) is selected from H, methyl, andethyl; R¹ is selected from a C₆₋₁₀ aryl group substituted with 0–5 R⁴;R² is selected from a C₆₋₁₀ aryl group substituted with 0–5 R⁵; R³ isselected from H, (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(3d),(CRR)_(q)S(O)_(p)R^(3d), (CRR)_(r)C(O)R^(3b), (CRR)_(q)NR^(3a)R^(3a),(CRR)_(r)C(O)NR^(3a)R^(3a), (CRR)_(r)C(O)NR^(3a)OR^(3d),(CRR)_(q)SO₂NR^(3a)R^(3a), (CRR)_(r)C(O)OR^(3d), a (CRR)_(r)—C₃₋₁₀carbocyclic residue substituted with 0–5 R^(3e); with the proviso thatR³ is not H if R⁶ is H; alternatively, R³ and R¹² join to form a C₃₋₆cycloalkyl substituted with 0–2 R^(3g); R^(3a), at each occurrence, isindependently selected from H, methyl substituted with 0–1 R^(3c), C₂₋₆alkyl substituted with 0–3 R^(3e), C₃₋₈ alkenyl substituted with 0–3R^(3e), C₃₋₈ alkynyl substituted with 0–3 R^(3e), (CH₂)_(r)C₃₋₆cycloalkyl, and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with0–5 R^(3e); R^(3b), at each occurrence, is independently selected fromC₁₋₆ alkyl substituted with 0–3 R^(3e), C₂₋₈ alkenyl substituted with0–3 R^(3e), C₂₋₈ alkynyl substituted with 0–3 R^(3e), and a(CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0–2 R^(3e); R^(3c)is independently selected from —C(O)R^(3b), —C(O)OR^(3d),—C(O)NR^(3f)R^(3f), and (CH₂)_(r)phenyl; R^(3d), at each occurrence, isindependently selected from H, methyl, —CF₃, C₂₋₆ alkyl substituted with0–3 R^(3e), C₃₋₆ alkenyl substituted with 0–3 R^(3e), C₃₋₆ alkynylsubstituted with 0–3 R^(3e), and a C₃₋₁₀ carbocyclic residue substitutedwith 0–3 R^(3e); R^(3e), at each occurrence, is selected from C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(3f)R^(3f), and (CH₂)_(r)phenyl; R^(3f), at each occurrence,is selected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R^(3g) is selectedfrom (CHR)_(r)OH, (CHR)_(r)SH, (CHR)_(r)OR^(3d),(CHR)_(r)S(O)_(r)R^(3d), (CHR)_(r)C(O)R^(3b), (CHR)_(r)NR^(3a)R^(3a),(CHR)_(r)C(O)NR^(3a)R^(3a), (CHR)_(r)C(O)NR^(3a)OR^(3d),(CHR)_(r)SO₂NR^(3a)R^(3a), (CHR)_(r)C(O)OR^(3d), and a (CHR)_(r)—C₃₋₁₀carbocyclic residue substituted with 0–5 R^(3e); R, at each occurrence,is independently selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, (CHR)_(r)C(O)NR^(3a)R^(3a),(CHR)_(r)C(O)OR^(3d), and (CH₂)_(r)phenyl substituted with 0–3 R^(3e);R⁴, at each occurrence, is selected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′)_(r)NR^(4a)R^(4a), (CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(4d),(CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(4d),(CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O) (CR′R′)_(r)R^(4b),(CR′R′)_(r)C(O)NR^(4a)R^(4a), (CR′R′)_(r)NR^(4f)C(O)(CR′R′)_(r)R^(4b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(4d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(4b),(CR′R′)_(r)NR^(4f)C(O)O(CR′R′)_(r)R^(4d), (CR′R′)_(r)OC(O)NR^(4a)R^(4a),(CR′R′)_(r)NR^(4a)C(S)NR^(4a)(CR′R′)_(r)R^(4d),(CR′R′)_(r)NR^(4a)C(O)NR^(4a)R^(4a),(CR′R′)_(r)C(═NR^(4f))NR^(4a)R^(4a),(CR′R′)_(r)NHC(═NR^(4f))NR^(4f)R^(4f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(4b), (CR′R′)_(r)S(O)₂NR^(4a)R^(4a),(CR′R′)_(r)NR^(4f)S(O)₂NR^(4a)R^(4a),(CR′R′)_(r)NR^(4f)S(O)₂(CR′R′)_(r)R^(4b), C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0–3 R′, C₂₋₈ alkynyl substituted with 0–3 R′, and(CR′R′)_(r)phenyl substituted with 0–3 R^(4e); alternatively, two R⁴ onadjacent atoms on R¹ may join to form a cyclic acetal; R^(4a), at eachoccurrence, is independently selected from H, methyl substituted with0–1R^(4g), C₂₋₆ alkyl substituted with 0–2 R^(4e), C₃₋₈ alkenylsubstituted with 0–2 R^(4e), C₃₋₈ alkynyl substituted with 0–2 R^(4e),and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0–5 R^(4e);R^(4b), at each occurrence, is selected from C₁₋₆ alkyl substituted with0–2 R^(4e), C₃₋₈ alkenyl substituted with 0–2 R^(4e), C₃₋₈ alkynylsubstituted with 0–2 R^(4e), and a (CH₂)_(r)C₃₋₆ carbocyclic residuesubstituted with 0–3 R^(4e); R^(4d), at each occurrence, is selectedfrom C₃₋₈ alkenyl substituted with 0–2 R^(4e), C₃₋₈ alkynyl substitutedwith 0–2 R^(4e), methyl, CF₃, C₂₋₆ alkyl substituted with 0–3 R^(4e),and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0–3 R^(4e);R^(4e), at each occurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂,(CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl; R^(4f), at each occurrence,is selected from H, C₁₋₅ alkyl, and C₃₋₆ cycloalkyl, and phenyl; R^(4g)is independently selected from —C(O)R^(4b), —C(O)OR^(4d),—C(O)NR^(4f)R^(4f), and (CH₂)_(r)phenyl; R⁵, at each occurrence, isselected from C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, Br, I, F, NO₂, CN, (CR′R′)_(r)NR^(5a)R^(5a),(CR′R′)_(r)OH, (CR′R′)_(r)O(CR′R′)_(r)R^(5d), (CR′R′)_(r)SH,(CR′R′)_(r)C(O)H, (CR′R′)_(r)S(CR′R′)_(r)R^(5d), (CR′R′)_(r)C(O)OH,(CR′R′)_(r)C(O)(CR′R′)_(r)R^(5b), (CR′R′)_(r)C(O)NR^(5a)R^(5a),(CR′R′)_(r)NR^(5f)C(O)(CR′R′)_(r)R^(5b),(CR′R′)_(r)C(O)O(CR′R′)_(r)R^(5d), (CR′R′)_(r)OC(O)(CR′R′)_(r)R^(5b),CR′R′)_(r)NR^(5f)C(O)O(CR′R′)_(r)R^(5d), (CR′R′)_(r)OC(O)NR^(5a)R^(5a),(CR′R′)_(r)NR^(5a)C(O)NR^(5a)R^(5a),(CR′R′)_(r)C(═NR^(5f))NR^(5a)R^(5a),(CR′R′)_(r)NHC(═NR^(5f))NR^(5f)R^(5f),(CR′R′)_(r)S(O)_(p)(CR′R′)_(r)R^(5b), (CR′R′)_(r)S(O)₂NR^(5a)R^(5a),(CR′R′)_(r)NR^(5a)S(O)₂NR^(5a)R^(5a),(CR′R′)_(r)NR^(5f)S(O)₂(CR′R′)_(r)R^(5b)C₁₋₆ haloalkyl, C₂₋₈ alkenylsubstituted with 0–3 R′, C₂₋₈ alkynyl substituted with 0–3 R′,(CR′R′)_(r)phenyl substituted with 0–3 R^(5e); alternatively, two R⁵ onadjacent atoms on R² may join to form a cyclic acetal; R^(5a), at eachoccurrence, is independently selected from H, methyl substituted with0–1 R^(5g), C₂₋₆ alkyl substituted with 0–2 R^(5e), C₃₋₈ alkenylsubstituted with 0–2 R^(5e), C₃₋₈ alkynyl substituted with 0–2 R^(5e),and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0–5 R^(5e);R^(5b), at each occurrence, is independently selected from C₁₋₆ alkylsubstituted with 0–2 R^(5e), C₃₋₈ alkenyl substituted with 0–2 R^(5e),C₃₋₈ alkynyl substituted with 0–2 R^(5e), and a (CH₂)_(r)C₃₋₆carbocyclic residue substituted with 0–3 R^(5e); R^(5d), at eachoccurrence, is independently selected from C₃₋₈ alkenyl substituted with0–2 R^(5e), C₃₋₈ alkynyl substituted with 0–2 R^(5e), methyl, CF₃, C₂₋₆alkyl substituted with 0–3 R^(5e), and a (CH₂)_(r)—C₃₋₁₀ carbocyclicresidue substituted with 0–3 R^(5e); R^(5e), at each occurrence, isselected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(5f)R^(5f), and(CH₂)_(r)phenyl; R^(5f), at each occurrence, is selected from H, C₁₋₅alkyl, and C₃₋₆ cycloalkyl, and phenyl; R^(5g) is independently selectedfrom —C(O)R^(5b), —C(O)OR^(5d), —C(O)NR^(5f)R^(5f), and (CH₂)_(r)phenyl;R′, at each occurrence, is selected from H, C₁₋₆ alkyl, C₂₋₈ alkenyl,C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, and (CH₂)_(r)phenyl substitutedwith R^(5e); R⁶, is selected from H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(6d),(CRR)_(q)S(O)_(p)R^(6d), (CRR)_(r)C(O)R^(6b), (CRR)_(r)NR^(6a)R^(6a),(CRR)_(r)C(O)NR^(6a)R^(6a), (CRR)_(r)C(O)NR^(6a)OR^(6d),(CRR)SO₂NR^(6a)R^(6a), (CRR)_(r)C(O)OR^(6d), and a (CRR)_(r)—C₃₋₁₀carbocyclic residue substituted with 0–5 R^(6e); alternatively, R⁶ andR⁷ join to form a C₃₋₆ cycloalkyl substituted with 0–2 R^(6g); R^(6a),at each occurrence, is independently selected from H, methyl, C₂₋₆ alkylsubstituted with 0–3 R^(6e), C₃₋₈ alkenyl substituted with 0–3 R^(6e),C₃₋₈ alkynyl substituted with 0–3 R^(6e), (CH₂)_(r)C₃₋₆ cycloalkyl, anda (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0–5 R^(6e);R^(6b), at each occurrence, is independently selected from C₁₋₆ alkylsubstituted with 0–3 R^(6e), C₂₋₈ alkenyl substituted with 0–3 R^(6e),C₂₋₈ alkynyl substituted with 0–3 R^(6e), and a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0–2 R^(6e); R^(6d), at eachoccurrence, is independently selected from H, methyl, —CF₃, C₂₋₆ alkylsubstituted with 0–3 R^(6e), C₃₋₆ alkenyl substituted with 0–3 R^(6e),C₃₋₆ alkynyl substituted with 0–3 R^(6e), and a C₃₋₁₀ carbocyclicresidue substituted with 0–3 R^(6e); R^(6e), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(6f)R^(6f), and(CH₂)_(r)phenyl; R^(6f), at each occurrence, is independently selectedfrom H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R^(6g) is selected from(CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(6d), (CHR)_(q)S(O)_(p)R^(6d),(CHR)_(r)C(O)R^(6b), (CHR)_(q)NR^(6a)R^(6a), (CHR)_(r)C(O)NR^(6a)R^(6a),(CHR)_(r)C(O)NR^(6a)OR^(6d), (CHR)_(q)SO₂NR^(6a)R^(6a),(CHR)_(r)C(O)OR^(6d), and a (CHR)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0–5 R^(6e); R⁷, is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CRR)_(q)OH, (CRR)_(q)SH, (CRR)_(q)OR^(7d),(CRR)_(q)S(O)_(p)R^(7d), (CRR)_(r)C(O)R^(7b), (CRR)_(r)NR^(7a)R^(7a),(CRR)_(r)C(O)NR^(7a)R^(7a), (CRR)_(r)C(O)NR^(7a)OR^(7d),(CRR)_(q)SO₂NR^(7a)R^(7a), (CRR)_(r)C(O)OR^(7d), and a (CRR)_(r)—C₃₋₁₀carbocyclic residue substituted with 0–5 R^(7e); R^(7a), at eachoccurrence, is independently selected from H, methyl, C₂₋₆ alkylsubstituted with 0–3 R^(7e), C₃₋₈ alkenyl substituted with 0–3 R^(7e),C₃₋₈ alkynyl substituted with 0–3 R^(7e), (CH₂)_(r)C₃₋₆ cycloalkyl, a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0–5 R^(7e); R^(7b),at each occurrence, is independently selected from C₁₋₆ alkylsubstituted with 0–3 R^(7e), C₂₋₈ alkenyl substituted with 0–3 R^(7e),C₂₋₈ alkynyl substituted with 0–3 R^(7e), and a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0–2 R^(7e); R^(7d), at eachoccurrence, is independently selected from H, methyl, —CF₃, C₂₋₆ alkylsubstituted with 0–3 R^(7e), C₃₋₆ alkenyl substituted with 0–3 R^(7e),C₃₋₆ alkynyl substituted with 0–3 R^(7e), and a C₃₋₁₀ carbocyclicresidue substituted with 0–3 R^(7e); R^(7e), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(7f)R^(7f), and(CH₂)_(r)phenyl; R^(7f), at each occurrence, is independently selectedfrom H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R⁸ is selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH,(CRR)_(r)OR^(8d), (CRR)_(r)S(O)_(p)R^(8d), (CRR)_(r)C(O)R^(8b),(CRR)_(r)NR^(8a)R^(8a), (CRR)_(r)C(O)NR^(8a)R^(8a),(CRR)_(r)C(O)NR^(8a)OR^(8d), (CRR)_(r)SO₂NR^(8a)R^(8a),(CRR)_(r)C(O)OR^(8d), and a (CRR)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0–5 R^(8e); alternatively, R⁸ and R⁹ join to form aC₃₋₆ cycloalkyl substituted with 0–2 R^(8g); R^(8a), at each occurrence,is independently selected from H, methyl, C₂₋₆ alkyl substituted with0–3 R^(8e), C₃₋₈ alkenyl substituted with 0–3 R^(8e), C₃₋₈ alkynylsubstituted with 0–3 R^(8e), (CH₂)_(r)C₃₋₆ cycloalkyl, and a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0–5 R^(8e); R^(8b),at each occurrence, is independently selected from C₁₋₆ alkylsubstituted with 0–3 R^(8e), C₂₋₈ alkenyl substituted with 0–3 R^(8e),C₂₋₈ alkynyl substituted with 0–3 R^(8e), and a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0–2 R^(8e); R^(8d), at eachoccurrence, is independently selected from H, methyl, —CF₃, C₂₋₆ alkylsubstituted with 0–3 R^(8e), C₃₋₆ alkenyl substituted with 0–3 R^(8e),C₃₋₆ alkynyl substituted with 0–3 R^(8e), and a C₃₋₁₀ carbocyclicresidue substituted with 0–3 R^(8e); R^(8e), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(8f)R^(8f), and(CH₂)_(r)phenyl; R^(8f), at each occurrence, is independently selectedfrom H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R^(8g) is selected from(CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(8d), (CHR)_(q)S(O)_(p)R^(8d),(CHR)_(r)C(O)R^(8b), (CHR)_(q)NR^(8a)R^(8a), (CHR)_(r)C(O)NR^(8a)R^(8a),(CHR)_(r)C(O)NR^(8a)OR^(8d), (CHR)_(q)SO₂NR^(8a)R^(8a),(CHR)_(r)C(O)OR^(8d), and a (CHR)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0–5 R^(8e); R⁹ is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(9d),(CRR)_(r)S(O)_(p)R^(9d), (CRR)_(r)C(O)R^(9b), (CRR)_(r)NR^(9a)R^(9a),(CRR)_(r)C(O)NR^(9a)R^(9a), (CRR)_(r)C(O)NR^(9a)OR^(9d),(CRR)_(r)SO₂NR^(9a)R^(9a), (CRR)_(r)C(O)OR^(9d), a (CRR)_(r)—C₃₋₁₀carbocyclic residue substituted with 0–5 R^(9e); R^(9a), at eachoccurrence, is independently selected from H, methyl, C₂₋₆ alkylsubstituted with 0–3 R^(9e), C₃₋₈ alkenyl substituted with 0–3 R^(9e),C₃₋₈ alkynyl substituted with 0–3 R^(9e), (CH₂)_(r)C₃₋₆ cycloalkyl, anda (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0–5 R^(9e);R^(9b), at each occurrence, is independently selected from C₁₋₆ alkylsubstituted with 0–3 R^(9e), C₂₋₈ alkenyl substituted with 0–3 R^(9e),C₂₋₈ alkynyl substituted with 0–3 R^(9e), and a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0–2 R^(9e); R^(9d), at eachoccurrence, is independently selected from H, methyl, —CF₃, C₂₋₆ alkylsubstituted with 0–3 R^(9e), C₃₋₆ alkenyl substituted with 0–3 R^(9e),C₃₋₆ alkynyl substituted with 0–3 R^(9e), and a C₃₋₁₀ carbocyclicresidue substituted with 0–3 R^(9e); R^(9e), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(9f)R^(9f), and(CH₂)_(r)phenyl; R^(9f), at each occurrence, is independently selectedfrom H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹⁰ is selected from H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH,(CRR)_(r)OR^(10d), (CRR)_(r)S(O)_(p)R^(10d), (CRR)_(r)C(O)R^(10b),(CRR)_(r)NR^(10a)R^(10a), (CRR)_(r)C(O)NR^(10a)R^(10a),(CRR)_(r)C(O)NR^(10a)OR^(10d), (CRR)_(r)SO₂NR^(10a)R^(10a),(CRR)_(r)C(O)OR^(10d), and a (CRR)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0–5 R^(10e); alternatively, R¹⁰ and R¹¹ join to form aC₃₋₆ cycloalkyl substituted with 0–2 R^(10g); R^(10a), at eachoccurrence, is independently selected from H, methyl, C₂₋₆ alkylsubstituted with 0–3 R^(10e), C₃₋₈ alkenyl substituted with 0–3 R^(10e),C₃₋₈ alkynyl substituted with 0–3 R^(10e), (CH₂)_(r)C₃₋₆ cycloalkyl, anda (CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0–5 R^(10e)R^(10b), at each occurrence, is independently selected from C₁₋₆ alkylsubstituted with 0–3 R^(10e), C₂₋₈ alkenyl substituted with 0–3 R^(10e),C₂₋₈ alkynyl substituted with 0–3 R^(10e), and a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0–2 R^(10e); R^(10d), at eachoccurrence, is independently selected from H, methyl, —CF₃, C₂₋₆ alkylsubstituted with 0–3 R^(10e), C₃₋₆ alkenyl substituted with 0–3 R^(10e),C₃₋₆ alkynyl substituted with 0–3 R^(10e), and a C₃₋₁₀ carbocyclicresidue substituted with 0–3 R^(10e); R^(10e), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(10f)R^(10f),and (CH₂)_(r)phenyl; R^(10f), at each occurrence, is independentlyselected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R^(10g) is selectedfrom (CHR)_(q)OH, (CHR)_(q)SH, (CHR)_(q)OR^(10d),(CHR)_(q)S(O)_(p)R^(10d), (CHR)_(r)C(O)R^(10b),(CHR)_(q)NR^(10a)R^(10a), (CHR)_(r)C(O)NR^(10a)R^(10a),(CHR)_(r)C(O)NR^(10a)OR^(10d), (CHR)_(q)SO₂NR^(10a)R^(10a),(CHR)_(r)C(O)OR^(10d), and a (CHR)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0–5 R^(10e); R¹¹, is selected from H, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, (CRR)_(r)OH, (CRR)_(r)SH, (CRR)_(r)OR^(11d),(CRR)_(r)S(O)_(p)R^(11d), (CRR)_(r)C(O)R^(11b),(CRR)_(r)NR^(11a)R^(11a), (CRR)_(r)C(O)NR^(11a)R^(11a),(CRR)_(r)C(O)NR^(11a)OR^(11d), (CRR)_(r)SO₂NR^(11a)R^(11a),(CRR)_(r)C(O)OR^(11d), and a (CRR)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0–5 R^(11e); R^(11a), at each occurrence, isindependently selected from H, methyl, C₂₋₆ alkyl substituted with 0–3R^(11e), C₃₋₈ alkenyl substituted with 0–3 R^(11e), C₃₋₈ alkynylsubstituted with 0–3 R^(11e), (CH₂)_(r)C₃₋₆ cycloalkyl, and a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0–5 R^(11e);R^(11b), at each occurrence, is independently selected from C₁₋₆ alkylsubstituted with 0–3 R^(11e), C₂₋₈ alkenyl substituted with 0–3 R^(11e),C₂₋₈ alkynyl substituted with 0–3 R^(11e), and a (CH₂)_(r)—C₃₋₆carbocyclic residue substituted with 0–2 R^(11e); R^(11d), at eachoccurrence, is independently selected from H, methyl, —CF₃, C₂₋₆ alkylsubstituted with 0–3 R^(11e), C₃₋₆ alkenyl substituted with 0–3 R^(11e),C₃₋₆ alkynyl substituted with 0–3 R^(11e), and a C₃₋₁₀ carbocyclicresidue substituted with 0–3 R^(11e); R^(11e), at each occurrence, isindependently selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl,OH, —O—C₁₋₆ alkyl, SH, (CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(11f)R^(11f),and (CH₂)_(r)phenyl; R^(11f), at each occurrence, is independentlyselected from H, C₁₋₆ alkyl, and C₃₋₆ cycloalkyl; R¹² is selected fromH, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, (CRR)_(q)OH, (CRR)_(q)SH,(CRR)_(q)OR^(12d), (CRR)_(q)S(O)_(p)R^(12d), (CRR)_(r)C(O)R^(12b),(CRR)_(r)NR^(12a)R^(12a), (CRR)_(r)C(O)NR^(12a)R^(12a),(CRR)_(r)C(O)NR^(12a)OR^(12d), (CRR)_(q)SO₂NR^(12a)R^(12a),(CRR)_(r)C(O)OR^(12d), and a (CRR)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0–5 R^(12e); R^(12a), at each occurrence, isindependently selected from H, methyl, C₂₋₆ alkyl substituted with 0–3R^(12e), C₃₋₈ alkenyl substituted with 0–3 R^(12e), C₃₋₈ alkynylsubstituted with 0–3 R^(12e), (CH₂)_(r)C₃₋₆ cycloalkyl, and a(CH₂)_(r)—C₃₋₁₀ carbocyclic residue substituted with 0–5 R^(12e)R^(12b), at each occurrence, is independently selected from C₁₋₆ alkylsubstituted with 0–3 R^(12e), C₂₋₈ alkenyl substituted with 0–3 R^(12e),C₂₋₈ alkynyl substituted with 0–3 R^(12e), a (CH₂)_(r)—C₃₋₆ carbocyclicresidue substituted with 0–2 R^(12e); R^(12d), at each occurrence, isindependently selected from H, methyl, —CF₃, C₂₋₆ alkyl substituted with0–3 R^(12e), C₃₋₆ alkenyl substituted with 0–3 R^(12e), C₃₋₆ alkynylsubstituted with 0–3 R^(12e), a C₃₋₁₀ carbocyclic residue substitutedwith 0–3 R^(12e); R^(12e), at each occurrence, is independently selectedfrom C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, C₃₋₆ cycloalkyl, Cl, F, Br,I, CN, NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, —O—C₁₋₁₆ alkyl, SH,(CH₂)_(r)SC₁₋₅ alkyl, (CH₂)_(r)NR^(12f)R^(12f), and (CH₂)_(r)phenyl;R^(12f), at each occurrence, is selected from H, C₁₋₆ alkyl, and C₃₋₆cycloalkyl; R¹⁴ and R^(14a) are independently selected from H, andC₁₋₄alkyl substituted with 0–1 R^(14b), and F; alternatively, R¹⁴ andR^(14a) can join to form a C₃₋₆ cycloalkyl; R^(14b), at each occurrence,is independently selected from —OH, —SH, —NR^(14c)R^(14c),—C(O)NR^(14c)R^(14c), —NHC(O)R^(14c) and phenyl; R^(14c) is selectedfrom H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹⁶ is selected from H, C₁₋₄alkyl substituted with 0–3 R^(16a), and C₃₋₆ cycloalkyl substituted with0–3 R^(16a); R^(16a) is selected from C₁₋₄ alkyl, —OH, —SH,—NR^(16c)R^(16c), —C(O)NR^(16c)R^(16c), and —NHC(O)R^(16c); R^(16c) isselected from H, C₁₋₄ alkyl and C₃₋₆ cycloalkyl; R¹⁷ is selected from H,C₁₋₄ alkyl, and C₃₋₄ cycloalkyl; R¹⁸ is selected from H, C₁₋₄ alkyl, andC₃₋₄ cycloalkyl; n is selected from 0, 1, and 2; l is selected from 0and 1; m is selected from 0 and 1; p, at each occurrence, is selectedfrom 0, 1, or 2; q, at each occurrence, is selected from 1, 2, 3, or 4;and r, at each occurrence, is selected from 0, 1, 2, 3, or
 4. 2. Thecompound of claim 1, wherein R¹⁴ and R^(14a) are independently selectedfrom H, and C₁₋₄alkyl substituted with 0–1 R^(14b); alternatively, R¹⁴and R^(14a) can join to form a C₃₋₆ cycloalkyl.
 3. The compound of claim2, wherein: R¹⁶ is selected from H, C₁₋₄ alkyl substituted with 0–1R^(16a), wherein the alkyl is selected from methyl, ethyl, propyl,i-propyl, butyl, i-butyl, and s-butyl, and C₃₋₄ cycloalkyl substitutedwith 0–3 R¹⁶a wherein the cycloalkyl is selected from cyclopropyl andcyclobutyl; R^(16a) is selected from methyl, ethyl, propyl, i-propyl,—OH, —SH, —NR^(16c)R^(16c), —C(O)NR^(16c)R^(16c), and —NHC(O)R^(16c);R^(16c) is selected from H, methyl, ethyl, propyl, i-propyl, butyl,cyclopropyl, cyclopentyl, and cyclohexyl; and R¹⁷ is selected from H,methyl, ethyl, propyl, and i-propyl.
 4. The compound of claim 3,wherein: R⁹ and R¹¹ are H; and R⁸ and R¹⁰ are independently selectedfrom H, methyl, ethyl, propyl, i-propyl, butyl, and cyclopropyl.
 5. Thecompound of claim 4, wherein: R³ is selected from (CRR)_(q)OH,(CRR)_(q)SH, (CRR)_(q)OR^(3d), (CRR)_(q)S(O)_(p)R^(3d),(CRR)_(r)C(O)R^(3b), (CRR)_(q)NR^(3a)R^(3a), (CRR)_(r)C(O)NR^(3a)R^(3a),(CRR)_(r)C(O)NR^(3a)OR^(3d), (CRR)_(q)SO₂NR^(3a)R^(3a),(CRR)_(r)C(O)OR^(3d), and a (CRR)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0–5 R^(3e); R⁶ is selected from H, (CRR)_(q)OH,(CRR)_(q)SH, (CRR)_(q)OR^(6d), (CRR)_(q)S(O)_(p)R^(6d),(CRR)_(r)C(O)R^(6b), (CRR)_(q)NR^(6a)R^(6a), (CRR)_(r)C(O)NR^(6a)R^(6a),(CRR)_(r)C(O)NR^(6a)OR^(6d), (CRR)_(q)SO₂NR^(6a)R^(6a),(CRR)_(r)C(O)OR^(6d), and a (CRR)_(r)—C₆₋₁₀ carbocyclic residuesubstituted with 0–5 R^(6e); R⁷ is H; R¹² is selected from H, methyl,ethyl, and propyl; alternatively, R³ and R¹² join to form a C₃₋₆cycloalkyl substituted with 0–2 R^(3g); m+1 is equal to 0 or
 1. 6. Thecompound of claim 5, wherein: R¹ is selected from phenyl substitutedwith 0–3 R⁴; and R² is selected from phenyl substituted with 0–3 R⁵. 7.The compound of claim 6, wherein: R⁴, at each occurrence, is selectedfrom C₁₋₈ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CR′R′)_(r)C₃₋₆ cycloalkyl,Cl, Br, I, F, NO₂, CN, (CR′R′)_(r)NR^(4a)R^(4a), (CR′R′)_(r)OH,(CR′R′)_(r)OR^(4d), (CR′R′)_(r)SH, (CR′R′)_(r)SR^(4d),(CR′R′)_(r)C(O)OH, (CR′R′)_(r)C(O)R^(4b), (CR′R′)_(r)C(O)NR^(4a)R^(4a),(CR′R′)_(r)NR^(4f)C(O)R^(4b), (CR′R′)_(r)C(O)OR^(4d),(CR′R′)_(r)OC(O)R^(4b), (CR′R′)_(r)NR^(4f)C(O)OR^(4d),(CR′R′)_(r)OC(O)NR^(4a)R^(4a), (CR′R′)_(r)NR^(4a)C(O)NR^(4a)R^(4a),(CR′R′)_(r)S(O)_(p)R^(4b), (CR′R′)_(r)S(O)₂NR^(4a)R^(4a),(CR′R′)_(r)NR^(4f)S(O)₂R^(4b), (CR′R′)_(r)NR^(4f)S(O)₂ NR^(4a)R^(4a),C₁₋₆ haloalkyl, and (CR′R′)_(r)phenyl substituted with 0–3 R^(4e);alternatively, two R⁴ on adjacent atoms join to form —O—(CH₂)—O—;R^(4a), at each occurrence, is independently selected from H, methyl,ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl,hexyl, allyl, propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residueselected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;R^(4b), at each occurrence, is selected from methyl, ethyl, propyl,i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl, allyl,propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue substituted with 0–3R^(4e), wherein the carbocyclic residue is selected from cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl; R^(4d), at each occurrence, isselected from H, methyl, CF₃, ethyl, propyl, i-propyl, butyl, s-butyl,i-butyl, t-butyl, pentyl, hexyl, allyl, propargyl, and a (CH₂)_(r)—C₃₋₆carbocyclic residue selected from cyclopropyl, cyclobutyl, cyclopentyland cyclohexyl; R^(4e), at each occurrence, is selected from C₁₋₆ alkyl,C₂₋₈ alkenyl, C₂₋₈ alkynyl, (CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN,NO₂, (CF₂)_(r)CF₃, (CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl; R^(4f), at each occurrence,is selected from H, methyl, ethyl, propyl, i-propyl, butyl, andcyclopropyl, cyclobutyl, and phenyl; R⁵, at each occurrence, is selectedfrom methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl,pentyl, hexyl, (CR′R′)_(r)C₃₋₆ cycloalkyl, Cl, Br, I, F, NO₂, CN,(CR′R′)_(r)NR^(5a)R^(5a), (CR′R′)_(r)OH, (CR′R′)_(r)OR^(5d),(CR′R′)_(r)SH, (CR′R′)_(r)C(O)H, (CR′R′)_(r)SR^(5d), (CR′R′)_(r)C(O)OH,(CR′R′)_(r)C(O)R^(5b), (CR′R′)_(r)C(O)NR^(5a)R^(5a),(CR′R′)_(r)NR^(5f)C(O)R^(5b), (CR′R′)_(r)C(O)OR^(5d),(CR′R′)_(r)OC(O)R^(5b), (CR′R′)_(r)NR^(5f)C(O)OR^(5d),(CR′R′)_(r)OC(O)NR^(5a)R^(5a), (CR′R′)_(r)NR^(5a)C(O)NR^(5a)R^(5a),(CR′R′)_(r)NR^(7a)C(O)NR^(7a)R^(7a),(CR′R′)_(r)NR^(7a)C(O)O(CR′R′)_(r)R^(7d), (CR′R′)_(r)S(O)_(p)R^(5b),(CR′R′)_(r)S(O)₂NR^(5a)R^(5a), (CR′R′′)_(r)NR^(5f)S(O)₂R^(5b), C₁₋₆haloalkyl, and (CHR′)_(r)phenyl substituted with 0–3 R^(5e);alternatively, two R⁵ on adjacent atoms join to form —O—(CH₂)—O—;R^(5a), at each occurrence, is independently selected from H, methyl,ethyl, propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl,hexyl, allyl, propargyl, and a (CH₂)_(r)—C₃₋₁₀ carbocyclic residuesubstituted with 0–1 R^(5e), wherein the carbocyclic residue is selectedfrom cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl andnaphthyl; R^(5b), at each occurrence, is selected from methyl, ethyl,propyl, i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl,allyl, propargyl, a (CH₂)_(r)—C₃₋₆ carbocyclic residue selected fromcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl; R^(5d), ateach occurrence, is selected from H, methyl, CF₃, ethyl, propyl,i-propyl, butyl, s-butyl, i-butyl, t-butyl, pentyl, hexyl, allyl,propargyl, and a (CH₂)_(r)—C₃₋₆ carbocyclic residue selected fromcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; R^(5e), at eachoccurrence, is selected from C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl,(CH₂)_(r)C₃₋₆ cycloalkyl, Cl, F, Br, I, CN, NO₂, (CF₂)_(r)CF₃,(CH₂)_(r)OC₁₋₅ alkyl, OH, SH, (CH₂)_(r)SC₁₋₅ alkyl,(CH₂)_(r)NR^(4f)R^(4f), and (CH₂)_(r)phenyl; and R^(5f), at eachoccurrence, is selected from H, methyl, ethyl, propyl, i-propyl, butyl,and cyclopropyl, cyclobutyl, and phenyl.
 8. The compound of claim 7,wherein: R⁵ is selected from methyl, ethyl, propyl, i-propyl, butyl,i-butyl, s-butyl, pentyl, hexyl, CF₃, CF₂CF₃, CF₂H, OCF₃, Cl, Br, I, F,SCF₃, NR^(5a)R^(5a), NHC(O)OR^(5a), NHC(O)R^(5b), and NHC(O)NHR^(5a);and R¹² is selected from H and methyl.
 9. A compound of claim 8,wherein: X is —CHR¹⁶NR¹⁷—; R¹ is selected from phenyl substituted with0–3 R⁴; R² is phenyl substituted with 0–2 R⁵; R³ is selected from(CRR)_(q)OH, (CRR)_(q)OR^(3d), (CH₂)_(r)C(O)OH,(CH₂)_(r)C(O)NR^(3a)R^(3a), (CHR)_(r)C(O)NR^(3a)OR^(3d),(CH₂)C(O)R^(3b), (CH₂)_(r)C(O)OR^(3d), and (CH₂)-phenyl; R^(3a) isselected from H, methyl, ethyl, propyl, i-propyl, butyl, i-butyl,s-butyl, t-butyl, allyl, CH₂CF₃, C(CH₃)CH₂CH₂OH, cyclopropyl,1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, andbenzyl; R^(3d) is selected from methyl, ethyl, propyl, i-propyl, butyl,i-butyl, t-butyl and benzyl; R is selected from H, methyl, ethyl,propyl, i-propyl, butyl, i-butyl, s-butyl, pentyl, neopentyl, phenyl andbenzyl; R⁴ is selected from methyl, ethyl, propyl, i-propyl, butyl,ethylene, OCH₃, OCF₃, SCH₃, SO₂CH₃, Cl, F, Br, CN; alternatively, two R⁴join to form —O—(CH₂)—O—; R⁶ is selected from H, methyl, ethyl, propyl,i-propyl, butyl, C(O)OCH₃, C(O)NHCH₂CH₃; R⁷ is H; R¹⁶ is selected from Hand methyl; R¹⁷ is selected from H and methyl; m is 0; l is 0 r is 0 or1; and q is
 1. 10. The compound of claim 1, wherein the compound isselected from:N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(2-trifluoromethyl-phenyl)-malonamide;N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-trifluoromethyl-phenyl)-malonamide;N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(4-trifluoromethyl-phenyl)-malonamide;[2-(2-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentylcarbamoyl}-acetylamino)-4-trifluoromethyl-phenyl]-carbamicacid tert-butyl ester;N-(2-Amino-5-trifluoromethyl-phenyl)-N′-{((1S,2S)-1-[(2,4-dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-malonamide;N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-trifluoromethoxy-phenyl)-malonamide;N-(3,5-Bis-trifluoromethyl-phenyl)-N′-{(1S,2S)-1-[(2,4-dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-malonamide;[3-(2-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentylcarbamoyl}-acetylamino)-5-trifluoromethyl-phenyl]-carbamicacid tert-butyl ester;N-(3-Amino-5-trifluoromethyl-phenyl)-N′-{(1S,2S)-1-[(2,4-dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-malonamide;N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-methoxy-5-trifluoromethyl-phenyl)-malonamide;N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(2-methoxy-5-trifluoromethyl-phenyl)-malonamide;N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-propylamino-5-trifluoromethyl-phenyl)-malonamide;N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-dipropylamino-5-trifluoromethyl-phenyl)-malonamide;N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-methylamino-5-trifluoromethyl-phenyl)-malonamide;N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-ethylamino-5-trifluoromethyl-phenyl)-malonamide;N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-[3-(3-ethyl-ureido)-5-trifluoromethyl-phenyl]-malonamide;N-{(1S,2S)-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(4-methyl-3-trifluoromethyl-phenyl)-malonamide;N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(4-methoxy-3-trifluoromethyl-phenyl)-malonamide;N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(2-methyl-5-trifluoromethyl-phenyl)-malonamide;N-(3-Bromo-5-trifluoromethyl-phenyl)-N′-{(1S,2S)-1-[(2,4-dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-malonamide;N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-dimethylcarbamoyl-5-trifluoromethyl-phenyl)-malonamide;N-{1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-N′-(3-ethylcarbamoyl-5-trifluoromethyl-phenyl)-malonamide;N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-2,2-dimethyl-N′-(3-trifluoromethyl-phenyl)-malonamide;N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-(2R/S)-2-methyl-N′-(3-trifluoromethyl-phenyl)-malonamide;N-{(1S,2S)-1-[(2,4-Dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-2,2-difluoro-N′-(3-trifluoromethyl-phenyl)-malonamide;andN-(3-Amino-5-trifluoromethyl-phenyl)-N′-{(1S,2S)-1-[(2,4-dimethyl-benzylamino)-methyl]-2-hydroxy-pentyl}-2,2-difluoro-malonamide.11. A pharmaceutical composition, comprising a pharmaceuticallyacceptable carrier and a therapeutically effective amount of a compoundof claim
 1. 12. A method for modulation of chemokine or chemokinereceptor activity comprising administering to a patient in need thereofa therapeutically effective amount of a compound of claim
 1. 13. Amethod for modulation of MCP-1, MCP-2, MCP-3 and MCP-4, and MCP-5activity that is mediated by the CCR2 receptor comprising administeringto a patient in need thereof a therapeutically effective amount of acompound of claim
 1. 14. A method for modulation of MCP-1 activitycomprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of claim
 1. 15. A method for treatingdisorders, comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim 1, saiddisorders being selected from multiple sclerosis, artherosclerosis,rheumatoid arthritis.
 16. A method for treating inflammatory diseases,comprising administering to a patient in need thereof a therapeuticallyeffective amount of a compound of claim
 1. 17. A method for modulationof CCR2 activity comprising administering to a patient in need thereof atherapeutically effective amount of a compound of claim 1.